Heterocycle derivatives useful as selective androgen receptor modulators (SARMS)

ABSTRACT

The present invention is directed to novel heterocycle derivatives, pharmaceutical compositions containing them and their use in the treatment of disorders and conditions modulated by the androgen receptor.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of parent application Ser. No.11/258,448, filed on Oct. 25, 2005, now U.S. Pat. No. 7,465,809, whichclaims the benefit of U.S. Provisional Application 60/628,337, filed onNov. 16, 2004, both of which are incorporated by reference herein intheir entirety.

FIELD OF THE INVENTION

The present invention is directed to novel heterocycle derivatives,pharmaceutical compositions containing them and their use in thetreatment of disorders mediated by one or more androgen receptors andprocesses for their preparation. The compounds of the present inventionare selective androgen receptor modulators (SARMs).

BACKGROUND OF THE INVENTION

Androgens are the anabolic steroid hormones of animals, controllingmuscle and skeletal mass, the maturation of the reproductive system, thedevelopment of secondary sexual characteristics and the maintenance offertility in the male. In women, testosterone is converted to estrogenin most target tissues, but androgens themselves may play a role innormal female physiology, for example, in the brain. The chief androgenfound in serum is testosterone, and this is the effective compound intissues such as the testes and pituitary. In prostate and skin,testosterone is converted to dihydrotestosterone (DHT) by the action of5α-reductase. DHT is a more potent androgen than testosterone because itbinds more strongly to the androgen receptor.

Like all steroid hormones, androgens bind to a specific receptor insidethe cells of target tissues, in this case the androgen receptor. This isa member of the nuclear receptor transcription factor family. Binding ofandrogen to the receptor activates it and causes it to bind to DNAbinding sites adjacent to target genes. From there it interacts withco-activator proteins and basic transcription factors to regulate theexpression of the gene. Thus, via its receptor, androgens cause changesin gene expression in cells. These changes ultimately have consequenceson the metabolic output, differentiation or proliferation of the cellthat are visible in the physiology of the target tissue.

Although modulators of androgen receptor function have been employedclinically for some time, both the steroidal (Basaria, S., Wahlstrom, J.T., Dobs, A. S., J. Clin Endocrinol Metab (2001), 86, pp 5108-5117;Shahidi, N. T., Clin Therapeutics, (2001), 23, pp 1355-1390), andnon-steroidal (Newling, D. W., Br. J. Urol., 1996, 77 (6), pp 776-784)compounds have significant liabilities related to their pharmacologicalparameters, including gynecomastia, breast tenderness and hepatoxicity.In addition, drug-drug interactions have been observed in patientsreceiving anticoagulation therapy using coumarins. Finally, patientswith aniline sensitivities could be compromised by the metabolites ofnon-steroidal antiandrogens.

Non-steroidal agonists and antagonists of the androgen receptor areuseful in the treatment of a variety of disorders and diseases. Moreparticularly, agonists of the androgen receptor could be employed in thetreatment of prostate cancer, benign prostatic hyperplasia, hirsutism inwomen, alopecia, anorexia nervosa, breast cancer and acne. Antagonistsof the androgen receptor could be employed in male contraception, maleperformance enhancement, as well as in the treatment of cancer, AIDS,cachexia, and other disorders.

Nonetheless, there exists a need for small molecule, non-steroidalantagonists of the androgen receptor. We now describe a novel series oftri-substituted pyrazole derivatives as androgen receptor modulators.

SUMMARY OF THE INVENTION

The present invention is directed to compounds of formula (I)

wherein

W is selected from the group consisting of O, S and NR^(F);

R^(F) is selected from the group consisting of hydrogen, hydroxy, cyano,C₁₋₄alkyl, C₁₋₄alkoxy and —SO₂—C₁₋₄alkyl;

R¹ is selected from the group consisting of C₁₋₄alkyl and halogenatedC₁₋₄alkyl;

R² is selected from the group consisting of hydrogen, C₁₋₄alkyl,halogenated C₁₋₄alkyl, —C(O)O—C₁₋₄alkyl, —C(O)—C₁₋₄alkyl and—C(O)-(halogenated C₁₋₄alkyl);

a is an integer from 0 to 1;

-   -   is selected from the group consisting of phenyl, pyridyl,        pyrazinyl, pyrimidinyl and pyridazinyl;

R³ is absent or selected from the group consisting of hydrogen, halogen,C₁₋₄alkyl, halogenated C₁₋₄alkyl, cyano, nitro, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, —O—C₁₋₄alkyl, —S(O)₀₋₂—C₁₋₄alkyl, —NRAC(O)_C₁₋₄alkyl, benzyl, —O-phenyl, —C(O)-phenyl and —S(O)₀₋₂-phenyl;wherein R^(A) is selected from hydrogen or C₁₋₄alkyl;

R⁴ absent or is selected from the group consisting of hydrogen, halogen,C₁₋₄alkyl, halogenated C₁₋₄alkyl, cyano, nitro, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, —O—C₁₋₄alkyl, —S(O)₀₋₂—C₁₋₄alkyl,—NR^(B)C(O)_C₁₋₄alkyl, benzyl, —O-phenyl, —C(O)-phenyl and—S(O)₀₋₂-phenyl; wherein R^(B) is selected from hydrogen or C₁₋₄alkyl;

provided that when

is phenyl then at least one of R³ or R⁴ is other than hydrogen;

R⁶ and R⁷ are each independently absent or selected from the groupconsisting of hydrogen halogen, C₁₋₄alkyl, C₂₋₄alkenyl, C₁₋₄alkoxy,cyano, —C(O)O—C₁₋₄alkyl and —S(O)₀₋₂—C₁₋₄alkyl;

provided further that R³ is absent when a nitrogen atom is present atthe 3-position of

provided further that R⁴ is absent when a nitrogen atom is present atthe 4-position of

provided further that R⁶ is absent when a nitrogen atom is present atthe 6-position of

provided further that R⁷ is absent when a nitrogen atom is present atthe 2-position of

is selected from the group consisting of

wherein R^(5′) is selected from the group consisting of halogen andC₁₋₄alkyl; and wherein R¹⁰ and R¹¹ are each independently selected fromhydrogen, C₁₋₄alkyl, benzyl or —C(O)—CF₃;

R⁵ is selected from the group consisting of hydrogen, carboxy, alkyl,halogenated C₁₋₄alkyl, hydroxy substituted C₁₋₄alkyl, cycloalkyl, aryl,aralkyl, heteroaryl, heteroaryl-alkyl-, heterocycloalkyl,heterocycloalkyl-alkyl-, —C(O)-alkyl, —C(O)-(halogenated C₁₋₄alkyl),—C(O)O—C₁₋₄alkyl, —C(O)O-aryl, —C₁₋₄alkyl-S(O)₀₋₂—C₁₋₄alkyl,t-butyl-dimethyl-silyl and trimethylsilyl;

wherein the aryl, cycloalkyl, heteroaryl or heterocycloalkyl, whetheralone or as part of a substituent group is optionally substituted withone or more substituents independently selected from the groupconsisting of halogen, hydroxy, C₁₋₄alkyl, C₁₋₄alkoxy, halogenatedC₁₋₄alkyl, halogenated C₁₋₄alkoxy, cyano, nitro, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, —NR^(C)—C(O)—C₁₋₄alkyl, NR^(C)—C(O)-(halogenatedC₁₋₄alkyl), —C(O)O—C₁₋₄alkyl, —S(O)₀₋₂—C₁₋₄alkyl, —SO₂—NR^(C)R^(D),trimethyl-silyl and t-butyl-dimethyl-silyloxy; wherein each R^(C) andR^(D) are each independently selected from hydrogen or C₁₋₄alkyl;

and pharmaceutically acceptable salts thereof.

The present invention is further directed to compounds of formula (II)

wherein

Z is selected from the group consisting of OR^(E), SR^(E) and N(R^(F))₂;

wherein R^(E) is selected from the group consisting of hydrogen andC₁₋₄alkyl;

wherein each R^(F) is independently selected from the group consistingof hydrogen, hydroxy, cyano, C₁₋₄alkyl, C₁₋₄alkoxy and —SO₂—C₁₋₄alkyl;

provided that when one R^(F) group is hydroxy or cyano, then the otherR^(F) group is hydrogen;

alternatively, the two R^(F) groups are taken together with the nitrogenatom to which they are bound to form a 5 to 6 membered, saturatedheterocyclic ring structure;

R¹ is selected from the group consisting of C₁₋₄alkyl and halogenatedC₁₋₄alkyl;

a is an integer from 0 to 1;

is selected from the group consisting of phenyl, pyridyl, pyrazinyl,pyrimidinyl and pyridazinyl;

R³ is absent or selected from the group consisting of hydrogen, halogen,C₁₋₄alkyl, halogenated C₁₋₄alkyl, cyano, nitro, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, —O—C₁₋₄alkyl, —S(O)₀₋₂—C₁₋₄alkyl,—NR^(A)—C(O)—C₁₋₄alkyl, benzyl, —O-phenyl, —C(O)-phenyl and—S(O)₀₋₂-phenyl; wherein R^(A) is selected from hydrogen or C₁₋₄alkyl;

R⁴ absent or is selected from the group consisting of hydrogen, halogen,C₁₋₄alkyl, halogenated C₁₋₄alkyl, cyano, nitro, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, —O—C₁₋₄alkyl, —S(O)₀₋₂—C₁₋₄alkyl, —NRBC(O)—C₁₋₄alkyl, benzyl, —O-phenyl, —C(O)-phenyl and —S(O)₀₋₂-phenyl;wherein R^(B) is selected from hydrogen or C₁₋₄alkyl;

provided that when

is phenyl then at least one of R³ or R⁴ is other than hydrogen;

R⁶ and R⁷ are each independently absent or selected from the groupconsisting of hydrogen halogen, C₁₋₄alkyl, C₂₋₄alkenyl, C₁₋₄alkoxy,cyano, —C(O)O—C₁₋₄alkyl and —S(O)₀₋₂—C₁₋₄alkyl;

provided further that R³ is absent when a nitrogen atom is present atthe 3-position of

provided further that R⁴ is absent when a nitrogen atom is present atthe 4-position of

provided further that R⁶ is absent when a nitrogen atom is present atthe 6-position of

provided further that R⁷ is absent when a nitrogen atom is present atthe 2-position of

is selected from the group consisting of

wherein R^(5′) is selected from the group consisting of halogen andC₁₋₄alkyl; and wherein R¹⁰ and R¹¹ are each independently selected fromhydrogen, C₁₋₄alkyl, benzyl or —C(O)—CF₃;

R⁵ is selected from the group consisting of hydrogen, carboxy, alkyl,halogenated C₁₋₄alkyl, hydroxy substituted C₁₋₄alkyl, cycloalkyl, aryl,aralkyl, heteroaryl, heteroaryl-alkyl-, heterocycloalkyl,heterocycloalkyl-alkyl-, —C(O)-alkyl, —C(O)-(halogenated C₁₋₄alkyl),—C(O)O—C₁₋₄alkyl, —C(O)O-aryl, —C₁₋₄alkyl-S(O)₀₋₂—C₁₋₄alkyl,t-butyl-dimethyl-silyl and trimethylsilyl;

wherein the aryl, cycloalkyl, heteroaryl or heterocycloalkyl, whetheralone or as part of a substituent group is optionally substituted withone or more substituents independently selected from the groupconsisting of halogen, hydroxy, C₁₋₄alkyl, C₁₋₄alkoxy, halogenatedC₁₋₄alkyl, halogenated C₁₋₄alkoxy, cyano, nitro, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, —NR^(C)—C(O)—C₁₋₄alkyl, NR^(C)—C(O)-(halogenatedC₁₋₄alkyl), —C(O)O—C₁₋₄alkyl, —S(O)₀₋₂—C₁₋₄alkyl, —SO₂—NR^(C)R^(D),trimethyl-silyl and t-butyl-dimethyl-silyloxy; wherein each R^(C) andR^(D) are each independently selected from hydrogen or C₁₋₄alkyl;

and pharmaceutically acceptable salts thereof.

The present invention is further directed to a tautomeric mixturecomprising

R^(F) is selected from the group consisting of hydrogen, hydroxy, cyano,C₁₋₄alkyl, C₁₋₄alkoxy and —SO₂—C₁₋₄alkyl;

R¹ is selected from the group consisting of C₁₋₄alkyl and halogenatedC₁₋₄alkyl;

a is an integer from 0 to 1;

is selected from the group consisting of phenyl, pyridyl, pyrazinyl,pyrimidinyl and pyridazinyl;

R³ is absent or selected from the group consisting of hydrogen, halogen,C₁₋₄alkyl, halogenated C₁₋₄alkyl, cyano, nitro, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, —O—C₁₋₄alkyl, —S(O)₀₋₂—C₁₋₄alkyl, —NRAC(O)_C₁₋₄alkyl, benzyl, —O-phenyl, —C(O)-phenyl and —S(O)₀₋₂-phenyl;wherein R^(A) is selected from hydrogen or C₁₋₄alkyl;

R⁴ absent or is selected from the group consisting of hydrogen, halogen,C₁₋₄alkyl, halogenated C₁₋₄alkyl, cyano, nitro, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, —O—C₁₋₄alkyl, —S(O)₀₋₂—C₁₋₄alkyl,—NR^(B)—C(O)—C₁₋₄alkyl, benzyl, —O-phenyl, —C(O)-phenyl and—S(O)₀₋₂-phenyl; wherein R^(B) is selected from hydrogen or C₁₋₄alkyl;

provided that when

is phenyl then at least one of R³ or R⁴ is other than hydrogen;

R⁶ and R⁷ are each absent or independently selected from the groupconsisting of hydrogen halogen, C₁₋₄alkyl, C₂₋₄alkenyl, C₁₋₄alkoxy,cyano, —C(O)O—C₁₋₄alkyl and —S(O)₀₋₂—C₁₋₄alkyl;

provided further that R³ is absent when a nitrogen atom is present atthe 3-position of

provided further that R⁴ is absent when a nitrogen atom is present atthe 4-position of

provided further that R⁶ is absent when a nitrogen atom is present atthe 6-position of

provided further that R⁷ is absent when a nitrogen atom is present atthe 2-position of

is selected from the group consisting of

wherein R^(5′) is selected from the group consisting of halogen andC₁₋₄alkyl; and wherein R¹⁰ and R¹¹ are each independently selected fromhydrogen, C₁₋₄alkyl, benzyl or —C(O)—CF₃;

R⁵ is selected from the group consisting of hydrogen, carboxy, alkyl,halogenated C₁₋₄alkyl, hydroxy substituted C₁₋₄alkyl, cycloalkyl, aryl,aralkyl, heteroaryl, heteroaryl-alkyl-, heterocycloalkyl,heterocycloalkyl-alkyl-, —C(O)-alkyl, —C(O)-(halogenated C₁₋₄alkyl),—C(O)O—C₁₋₄alkyl, —C(O)O-aryl, —C₁₋₄alkyl-S(O)₀₋₂—C₁₋₄alkyl,t-butyl-dimethyl-silyl and trimethylsilyl;

wherein the aryl, cycloalkyl, heteroaryl or heterocycloalkyl, whetheralone or as part of a substituent group is optionally substituted withone or more substituents independently selected from the groupconsisting of halogen, hydroxy, C₁₋₄alkyl, C₁₋₄alkoxy, halogenatedC₁₋₄alkyl, halogenated C₁₋₄alkoxy, cyano, nitro, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, —NR^(C)—C(O)—C₁₋₄alkyl, NR^(C)—C(O)-(halogenatedC₁₋₄alkyl), —C(O)O—C₁₋₄alkyl, —S(O)₀₋₂—C₁₋₄alkyl, —SO₂—NR^(C)R^(D),trimethyl-silyl and t-butyl-dimethyl-silyloxy; wherein each R^(C) andR^(D) are each independently selected from hydrogen or C₁₋₄alkyl;

or a pharmaceutically acceptable salt thereof.

Illustrative of the invention is a pharmaceutical composition comprisinga pharmaceutically acceptable carrier and any of the compounds describedherein. An illustration of the invention is a pharmaceutical compositionmade by mixing any of the compounds described herein and apharmaceutically acceptable carrier. Illustrating the invention is aprocess for making a pharmaceutical composition comprising mixing any ofthe compounds described herein and a pharmaceutically acceptablecarrier.

Exemplifying the invention are methods of treating disorders andconditions modulated by the androgen receptor comprising administeringto a subject in need thereof a therapeutically effective amount of anyof the compounds or pharmaceutical compositions described herein.

An example of the invention is a method for treating an androgenreceptor modulated disorder selected from the group consisting ofprostate carcinoma, benign prostatic hyperplasia, hirsutism, or for malecontraception, comprising administering to a subject in need thereof aneffective amount of any of the compounds or pharmaceutical compositionsdescribed herein.

Another example of the invention is the use of any of the compoundsdescribed herein in the preparation of a medicament for treating: (a)prostate carcinoma, (b) benign prostatic hyperplasia, (c) hirsutism, (d)alopecia, (e) anorexia nervosa, (f) breast cancer, (g) acne, (h) AIDS,(i) cachexia, for (j) male contraception, or for (k) male performanceenhancement, in a subject in need thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of formula (I) andcompounds of formula (II)

wherein R¹, R², R³, R⁴, R⁶, R⁷, W, Z, a,

are as herein defined, useful as selective androgen receptor modulatorsfor the treatment of prostate carcinoma, benign prostatic hyperplasia(BPH), hirsutism, alopecia, anorexia nervosa, breast cancer, acne, AIDS,cachexia, as a male contraceptive, and/or as a male performanceenhancer.

The present invention is further directed to tautomeric mixturescomprising a compound of formula (It) and a compound of formula (IIt)

wherein R¹, R³, R⁴, R⁶, R⁷, R^(F), a,

are as herein defined, useful as selective androgen receptor modulatorsfor the treatment of prostate carcinoma, benign prostatic hyperplasia(BPH), hirsutism, alopecia, anorexia nervosa, breast cancer, acne, AIDS,cachexia, as a male contraceptive, and/or as a male performanceenhancer.

One skilled in the art will recognize that some of the variables (e.g.R¹, R², R³, a, etc.) appear in compounds of formula (I) and compounds offormula (II). One skilled in the art will further recognize that whereina particular substituent is selected for a given variable for a compoundof formula (I), said selection is not intended to limit the scope ofsaid variable for compounds of formula (II). Similarly, the selection ofa particular substituent for a given variable for a compound of formula(II), is not intended to limit the scope of said variable for compoundsof formula (I).

One skilled in the art will recognize that when in the compound offormula (I) R² is hydrogen and W is NR^(F) and in the compound offormula (II) Z is NHR^(F), then the corresponding compound of formula(I) and the corresponding compound formula (II) are tautomers. Oneskilled in the art will further recognize that in solution, thetautomers may exist as a mixture of varying ratios, depending on thenature of the solvent. Upon isolation as a solid, only one of thetautomers is isolated, although which tautomer was isolated was notdetermined for the compounds of the instant application.

In an embodiment, the present invention is directed to compounds offormula (I)

wherein

R¹ is selected from the group consisting of C₁₋₄alkyl and halogenatedC₁₋₄alkyl;

R² is selected from the group consisting of hydrogen, C₁₋₄alkyl and—C(O)O—C₁₋₄alkyl;

a is an integer from 0 to 1;

is selected from the group consisting of phenyl, pyridyl, pyrazinyl,pyrimidinyl and pyridazinyl;

R³ is absent or selected from the group consisting of hydrogen, halogen,C₁₋₄alkyl, halogenated C₁₋₄alkyl, cyano, nitro, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, —O—C₁₋₄alkyl, —S(O)₀₋₂—C₁₋₄alkyl, —NR^(A—C(O)—C)₁₋₄alkyl, benzyl, —O-phenyl, —C(O)-phenyl and —S(O)₀₋₂-phenyl; whereinR^(A) is selected from hydrogen or C₁₋₄alkyl;

R⁴ absent or is selected from the group consisting of hydrogen, halogen,C₁₋₄alkyl, halogenated C₁₋₄alkyl, cyano, nitro, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, —O—C₁₋₄alkyl, —S(O)₀₋₂—C₁₋₄alkyl, —NRBC(O)—C₁₋₄alkyl, benzyl, —O-phenyl, —C(O)-phenyl and —S(O)₀₋₂-phenyl;wherein R^(B) is selected from hydrogen or C₁₋₄alkyl;

provided that when

is phenyl then at least one of R³ or R⁴ is other than hydrogen;

provided further that R³ is absent when a nitrogen atom is present atthe 3-position of

provided further that R⁴ is absent when a nitrogen atom is present atthe 4-position of

is selected from the group consisting of

wherein R¹⁰ and R¹¹ are each independently selected from hydrogen,C₁₋₄alkyl or benzyl;

R⁵ is selected from the group consisting of hydrogen, carboxy, alkyl,halogenated C₁₋₄alkyl, hydroxy substituted C₁₋₄alkyl, cycloalkyl, aryl,aralkyl, heteroaryl, heteroaryl-alkyl-, heterocycloalkyl,heterocycloalkyl-alkyl-, —C(O)-alkyl, —C(O)-(halogenated C₁₋₄alkyl),—C(O)O—C₁₋₄alkyl, —C(O)O-aryl, —C₁₋₄alkyl-S(O)₀₋₂—C₁₋₄alkyl,t-butyl-dimethyl-silyl and trimethylsilyl;

wherein the aryl, cycloalkyl, heteroaryl or heterocycloalkyl, whetheralone or as part of a substituent group is optionally substituted withone or more substituents independently selected from the groupconsisting of halogen, hydroxy, C₁₋₄alkyl, C₁₋₄alkoxy, halogenatedC₁₋₄alkyl, halogenated C₁₋₄alkoxy, cyano, nitro, amino, C₁₋₄alkylamino,di(C₁₋₄alkyl)amino, —NR^(C)—C(O)—C₁₋₄alkyl, NR^(C)—C(O)-(halogenatedC₁₋₄alkyl), —C(O)O—C₁₋₄alkyl, —S(O)₀₋₂—C₁₋₄alkyl, —SO₂—NR^(C)R^(D),trimethyl-silyl and t-butyl-dimethyl-silyloxy; wherein each R^(C) andR^(D) are each independently selected from hydrogen or C₁₋₄alkyl;

and pharmaceutically acceptable salts thereof.

In an embodiment of the present invention, W is selected from the groupconsisting of O, S and NR^(F); wherein R^(F) is selected from the groupconsisting of hydrogen, hydroxy, C₁₋₄alkyl, C₁₋₄alkoxy, cyano and—SO₂—C₁₋₄alkyl. In another embodiment of the present invention, W isselected from the group consisting of O, S and NR^(F); wherein R^(F) isselected from the group consisting of hydrogen, hydroxy, C₁₋₄alkyl,C₁₋₂alkoxy, cyano and —SO₂—C₁₋₂alkyl. In another embodiment of thepresent invention, W is selected from the group consisting of O, S andNR^(F); wherein R^(F) is selected from the group consisting of hydrogen,hydroxy, methyl, ethyl, methoxy, cyano and —SO₂-methyl. In anotherembodiment of the present invention, W is selected from the groupconsisting of O, S and NR^(F); wherein R^(F) is selected from the groupconsisting of hydrogen, methyl, ethyl, methoxy, cyano and —SO₂-methyl.

In an embodiment of the present invention, W is selected from the groupconsisting of O, NH, N(OH), N(ethyl) and N(methoxy). In anotherembodiment of the present invention, W is selected from the groupconsisting of O and N(ethyl).

In an embodiment of the present invention W is selected from the groupconsisting of O and S. Preferably W is O. In another embodiment of thepresent invention W is selected from the group consisting of O andNR^(F). In another embodiment of the present invention W is NR^(F).Preferably, W is NR^(F) and R^(F) is selected form the group consistingof hydrogen, hydroxy, cyano, C₁₋₄alkyl and —SO²—C₁₋₄alkyl. Morepreferably, W is NR^(F) and R^(F) is selected form the group consistingof hydrogen, hydroxy, cyano, methyl, ethyl and —SO₂-methyl.

In an embodiment of the present invention, Z is selected from the groupconsisting of —O-methyl, —O-ethyl, —S-ethyl, —NH₂, —NH(OH), —NH-ethyl,—N(ethyl)₂ and —NH(OCH₃).

In an embodiment of the present invention, R^(E) is selected from thegroup consisting of hydrogen and C₁₋₄alkyl. In another embodiment of thepresent invention, R^(E) is selected from the group consisting ofC₁₋₄alkyl. In another embodiment of the present invention, R^(E) isselected from the group consisting of methyl and ethyl.

In an embodiment of the present invention, each R^(F) is independentlyselected from the group consisting of hydrogen, hydroxy, cyano,C₁₋₄alkyl, C₁₋₄alkoxy and —SO₂—C₁₋₄alkyl. In another embodiment of thepresent invention, each R^(F) is independently selected from the groupconsisting of hydrogen, hydroxy, cyano, C₁₋₄alkyl, C₁₋₂alkoxy and—SO₂—C₁₋₂alkyl. In another embodiment of the present invention, R^(F) isindependently selected from the group consisting of hydrogen, hydroxy,cyano, methyl, ethyl, methoxy and —SO₂-methyl.

In an embodiment of the present invention, the two R^(F) groups aretaken together with the nitrogen atom to which they are bound to form a5 to 6 membered, saturated heterocyclic ring structure. In anotherembodiment of the present invention, the two R^(F) groups are takentogether with the nitrogen atom to which they are bound to form1-pyrrolidinyl or 1-piperidinyl. In another embodiment of the presentinvention, the two R^(F) groups are taken together with the nitrogenatom to which they are bound to form 1-pyrrolidinyl.

In an embodiment of the present invention, R¹ is selected from the groupconsisting of C₁₋₄alkyl and halogenated C₁₋₄alkyl. In another embodimentof the present invention, R¹ is selected from the group consisting ofC₁₋₄alkyl and halogenated C₁₋₂alkyl. In another embodiment of thepresent invention, R¹ is selected from the group consisting of methyl,(S)-methyl, (R)-methyl, ethyl, n-propyl and trifluoromethyl. In anotherembodiment of the present invention, R¹ is selected from the groupconsisting of methyl, (R)-methyl, (S)-methyl, ethyl and trifluoromethyl.

In an embodiment of the present invention, R¹ is selected from the groupconsisting of C₁₋₂alkyl and halogenated C₁₋₂alkyl. In another embodimentof the present invention, R¹ is selected from the group consisting ofC₁₋₂alkyl. In another embodiment of the present invention, R¹ isselected from the group consisting of methyl, (R)-methyl and (S)-methyl.In another embodiment of the present invention, R¹ is selected from thegroup consisting of methyl and (S)-methyl.

In an embodiment of the present invention, R¹ is selected from the groupconsisting of C₁₋₂alkyl and halogenated C₁₋₂alkyl. In another embodimentof the present invention, R¹ is selected from the group consisting ofC₁₋₄alkyl. In another embodiment of the present invention, R¹ isselected from the group consisting of methyl, ethyl and n-propyl.Preferably, R¹ is selected from the group consisting of methyl, ethyland n-propyl. More preferably, R¹ is selected from the group consistingof methyl, (R)-methyl, (S)-methyl and ethyl. More preferably still, R¹is methyl.

In an embodiment of the present invention, R² is selected from the groupconsisting of hydrogen and C₁₋₄alkyl. In another embodiment of thepresent invention, R² is selected from the group consisting of hydrogenand methyl. Preferably, R² is hydrogen.

In an embodiment of the present invention, R² is selected from the groupconsisting of hydrogen, C₁₋₄alkyl, halogenated C₁₋₄alkyl and—C(O)-(halogenated C₁₋₄alkyl). In another embodiment of the presentinvention, R² is selected from the group consisting of hydrogen,C₁₋₄alkyl, halogenated C₁₋₂alkyl and —C(O)-(halogenated C₁₋₂alkyl). Inanother embodiment of the present invention, R² is selected from thegroup consisting of hydrogen, methyl, trifluoroethyl and —C(O)—CF₃.

In an embodiment of the present invention, a is 1. In another embodimentof the present invention, a is 0.

In an embodiment of the present invention,

is selected from the group consisting of phenyl and pyridyl. In anotherembodiment,

is selected from the group consisting of phenyl, 3-pyridyl and4-pyridyl. Preferably,

is phenyl. In another embodiment of the present invention,

is pyridyl. In yet another embodiment of the present invention,

is selected from the group consisting of 3-pyridyl and 4-pyridyl.

In an embodiment of the present invention, R³ is absent or selected fromthe group consisting of hydrogen, halogen, halogenated C₁₋₄alkyl, cyano,nitro, benzyl, —O-phenyl, —C(O)-phenyl, —S(O)₀₋₂—C₁₋₄alkyl and—S(O)₀₋₂-phenyl. In another embodiment of the present invention, R³ isabsent or selected from the group consisting of hydrogen, halogen,halogenated C₁₋₄alkyl and cyano. Preferably, R³ is absent or selectedfrom the group consisting of hydrogen, chloro, trifluoromethyl andcyano.

In an embodiment of the present invention, R³ is selected from the groupconsisting of hydrogen, halogen, halogenated C₁₋₄alkyl and cyano. Inanother embodiment of the present invention, R³ is selected from thegroup consisting of hydrogen, chloro, trifluoromethyl and cyano.Preferably, R³ is selected from the group consisting of hydrogen andtrifluoromethyl. More preferably, R³ is trifluoromethyl.

In an embodiment of the present invention, R³ is absent or hydrogen.

In an embodiment of the present invention, R³ is absent or selected fromthe group consisting of hydrogen, halogen and halogenated C₁₋₂alkyl. Inanother embodiment of the present invention, R³ is halogenatedC₁₋₂alkyl. In another embodiment of the present invention, R³ istrifluoromethyl.

In an embodiment of the present invention, R⁴ is selected from the groupconsisting of hydrogen, halogen, halogenated C₁₋₄alkyl, cyano, nitro,benzyl, —O-phenyl, —C(O)-phenyl, —S(O)₀₋₂—C₁₋₄alkyl and —S(O)₀₋₂-phenyl.In another embodiment of the present invention, R⁴ is absent or selectedfrom the group consisting of halogen, cyano, nitro, benzyl, —O-phenyl,—C(O)-phenyl, —S(O)₀₋₂—C₁₋₄alkyl and —S(O)₀₋₂-phenyl. Preferably, R⁴ isabsent or selected from the group consisting of chloro, bromo, cyano,nitro, benzyl, —O-phenyl, —S-phenyl, —C(O)-phenyl, —SO₂-methyl and—SO₂-phenyl.

In an embodiment of the present invention, R⁴ is selected from the groupconsisting of chloro, bromo, cyano, nitro, benzyl, —O-phenyl, —S-phenyl,—C(O)-phenyl, —SO₂-methyl and —SO₂-phenyl. In another embodiment of thepresent invention, R⁴ is selected from the group consisting of halogen,cyano, nitro, benzyl, —O-phenyl, —C(O)-phenyl, —S(O)₀₋₂—C₁₋₄alkyl and—S(O)₀₋₂-phenyl. Preferably, R⁴ is selected from the group consisting ofbromo, cyano, nitro and —SO₂-phenyl. More preferably, R⁴ is selectedfrom the group consisting of chloro, cyano and nitro.

In an embodiment of the present invention, R⁴ absent or is selected fromthe group consisting of cyano and halogen. In another embodiment of thepresent invention, R⁴ absent or is selected from the group consisting ofcyano and chloro.

In an embodiment of the present invention, R⁴ is absent or selected fromthe group consisting of hydrogen, halogen, halogenated C₁₋₂alkyl andcyano. In another embodiment of the present invention, R⁴ is cyano. Inan embodiment of the present invention, R⁶ and R⁷ are each independentlyabsent or selected from the group consisting of hydrogen, halogen,C₁₋₄alkyl, C₁₋₄alkoxy, cyano, —C(O)O—C₁₋₄alkyl and —S(O)₀₋₂—C₁₋₄alkyl.

In another embodiment of the present invention, R⁶ and R⁷ are eachindependently absent or selected from the group consisting of hydrogen,halogen, C₁₋₂alkyl, C₁₋₂alkoxy, cyano, —C(O)O—C₁₋₂alkyl, —S—C₁₋₄alkyland —SO₂—C₁₋₄alkyl. In another embodiment of the present invention, R⁶and R⁷ are each independently absent or selected from the groupconsisting of hydrogen, halogen, C₁₋₄alkyl and halogenated C₁₋₂alkyl.

In an embodiment of the present invention, R⁶ is selected from the groupconsisting of hydrogen, chloro, iodo, ethyl, methoxy, cyano,—C(O)O-methyl, —S-ethyl, —S-t-butyl and —SO₂-ethyl. In anotherembodiment of the present invention, R⁶ is selected from the groupconsisting of hydrogen, iodo, chloro and —S-ethyl. In another embodimentof the present invention, R⁶ is selected from the group consisting ofhydrogen, chloro, ethyl and —SO₂-ethyl. In another embodiment of thepresent invention, R⁶ is hydrogen.

In an embodiment of the present invention, R⁷ is selected from the groupconsisting of hydrogen, chloro and ethyl. In another embodiment of thepresent invention, R⁷ is selected from the group consisting of hydrogenand ethyl. In another embodiment of the present invention, R⁷ ishydrogen.

In an embodiment of the present invention,

is selected from the group consisting of

In another embodiment of the present invention,

is selected from the group consisting of

In another embodiment of the present invention,

is selected from the group consisting of

In another embodiment of the present invention,

is selected from the group consisting of

In another embodiment of the present invention,

is selected from the group consisting of

In another embodiment of the present invention,

In an embodiment of the present invention,

is selected from the group consisting of

In another embodiment of the present invention,

is selected from the group consisting of

Preferably,

In an embodiment of the present invention,

is selected from the group consisting of

In another embodiment of the present invention,

is selected from the group consisting of

In yet another embodiment of the present invention,

is selected from the group consisting of

In yet another embodiment of the present invention,

is selected from the group consisting of

In an embodiment of the present invention, R^(5′) is selected from thegroup consisting of halogen and C₁₋₂alkyl. In another embodiment of thepresent invention, R^(5′) is selected from the group consisting ofhalogen and C₁₋₄alkyl. In another embodiment of the present invention,R^(5′) is selected from the group consisting of halogen and C₁₋₂alkyl.In another embodiment, R^(5′) is selected from the group consisting ofchloro, bromo, idoo, methyl and ethyl. Preferably, R^(5′) is chloro ormethyl, more preferably, R^(5′) is chloro.

In an embodiment of the present invention R¹⁰ and R¹¹ are eachindependently selected from the group consisting of hydrogen, methyl andbenzyl. Preferably, R¹⁰ and R¹¹ are each independently selected from thegroup consisting of hydrogen and methyl.

In an embodiment of the present invention, R¹⁰ is selected fromhydrogen, C₁₋₄alkyl, benzyl or —C(O)—CF₃. In another embodiment of thepresent invention, R¹⁰ is selected from the group consisting ofhydrogen, C₁₋₄alkyl, benzyl and —C(O)—CF₃. In another embodiment of thepresent invention, R¹⁰ is selected from the group consisting ofhydrogen, C₁₋₂alkyl and benzyl. In another embodiment of the presentinvention, R¹⁰ is selected from the group consisting of hydrogen, methyland benzyl. In another embodiment of the present invention, R¹⁰ isselected from the group consisting of hydrogen and C₁₋₄alkyl. In anotherembodiment of the present invention, R¹⁰ is selected from the groupconsisting of hydrogen, methyl and ethyl. In another embodiment of thepresent invention, R¹⁰ is selected from the group consisting of hydrogenand ethyl. In another embodiment of the present invention, R¹⁰ isselected from the group consisting of hydrogen and methyl. Preferably,R¹⁰ is hydrogen.

In an embodiment of the present invention, R⁵ is selected from the groupconsisting of hydrogen, carboxy, alkyl, halogenated C₁₋₄alkyl, hydroxysubstituted C₁₋₄alkyl, cycloalkyl, aryl, aralkyl, heteroaryl,heterocycloalkyl, —C(O)—C₁₋₄alkyl, —C(O)-(halogenated C₁₋₄alkyl),—C(O)O—C₁₋₄alkyl, —C(O)O-aryl, —C₁₋₄alkyl-S(O)₀₋₂—C₁₋₄alkyl,t-butyl-dimethyl-silyl and trimethylsilyl;

wherein the aryl, heteroaryl or heterocycloalkyl, whether alone or aspart of a substituent group is optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, hydroxy, C₁₋₄alkyl, C₁₋₄alkoxy, halogenated C₁₋₄alkyl, cyano,nitro, —NR^(C)—C(O)—C₁₋₄alkyl, NR^(C)—C(O)-(halogenated C₁₋₄alkyl),—C(O)O—C₁₋₄alkyl, trimethyl-silyl and t-butyl-dimethyl-silyloxy; whereinR^(C) and R^(D) are each independently selected from hydrogen orC₁₋₄alkyl.

In another embodiment of the present invention, R⁵ is selected from thegroup consisting of hydrogen, carboxy, C₁₋₄alkyl, halogenated C₁₋₄alkyl,—C₁₋₄alkyl-OH, cycloalkyl, aryl, aralkyl, heteroaryl, heterocycloalkyl,—C₁₋₄alkyl-S—C₁₋₄alkyl, —C(O)O—C₁₋₄alkyl, —C(O)-(halogenated C₁₋₄alkyl)and trimethylsilyl;

wherein the aryl, whether alone or as part of a substituent group isoptionally substituted with one or more substituents independentlyselected from hydroxy, halogen, C₁₋₄alkyl, —O—C₁₋₄alkyl,—C(O)O—C₁₋₄alkyl, —NH—C(O)—C₁₋₄alkyl, —NH—C(O)-(halogenated C₁₋₄alkyl)or t-butyl-dimethyl-silyloxy.

In another embodiment of the present invention, R⁵ is selected from thegroup consisting of hydrogen, carboxy, methyl, ethyl, n-propyl,isopropyl, isobutyl, t-butyl, trifluoromethyl, 2,2,2-trifluoro-ethyl,1,1,2,2,2-pentafluoro-ethyl, hydroxy-methyl-, 2-hydroxy-phenyl,4-fluorophenyl, 3,4-difluorophenyl, 2,3,4,5,6-pentafluorophenyl,4-ethylphenyl, 4-methoxy-phenyl, 2-hydroxy-3-fluoro-phenyl,2-fluoro-3-hydroxy-phenyl, 3-methyl-4-fluoro-phenyl, cyclopentyl,cyclohexyl, 4-methoxy-carbonyl-phenyl, 3-methyl-carbonyl-amino-phenyl,4-methyl-carbonyl-amino-phenyl,4-(trifluoromethyl-carbonyl-amino)-phenyl,2-(t-butyl-dimethyl-silyloxy)-3-fluoro-phenyl,t-butyl-dimethyl-silyloxy-phenyl, 4-methyl-carbonyl-amino-benzyl,4-methyl-carbonyl-amino-phenyl, 2-furyl, 2-thienyl, 3-pyridyl,2-tetrahydrofuryl, methyl-thio-ethyl-, ethyl-thio-ethyl-,ethoxy-carbonyl-, t-butoxy-carbonyl-, trifluoromethyl-carbonyl- andtrimethylsilyl.

Preferably, R⁵ is selected from the group consisting of hydrogen,carboxy, methyl, ethyl, n-propyl, isopropyl, isobutyl, t-butyl,trifluoromethyl, 2,2,2-trifluoro-ethyl, 1,1,2,2,2-pentafluoro-ethyl,hydroxy-methyl-, 2-hydroxy-phenyl, 4-fluorophenyl, 3,4-difluorophenyl,2,3,4,5,6-pentafluorophenyl, 4-ethylphenyl, 4-methoxy-phenyl,2-hydroxy-3-fluoro-phenyl, 2-fluoro-3-hydroxy-phenyl,3-methyl-4-fluoro-phenyl, cyclopentyl, cyclohexyl,4-methoxy-carbonyl-phenyl, 3-methyl-carbonyl-amino-phenyl,4-methyl-carbonyl-amino-phenyl,4-(trifluoromethyl-carbonyl-amino)-phenyl,2-(t-butyl-dimethyl-silyloxy)-3-fluoro-phenyl,t-butyl-dimethyl-silyloxy-phenyl, 4-methyl-carbonyl-amino-benzyl,2-furyl, 2-thienyl, 3-pyridyl, 2-tetrahydrofuryl, methyl-thio-ethyl-,ethyl-thio-ethyl-, ethoxy-carbonyl-, t-butoxy-carbonyl-,trifluoromethyl-carbonyl- and trimethylsilyl.

In a embodiment of the present invention, R⁵ is selected from the groupconsisting of halogenated C₁₋₂alkyl. In another embodiment of thepresent invention, R⁵ is trifluoromethyl. In another embodiment of thepresent invention, R⁵ is selected from the group consisting ofhalogenated C₁₋₄alkyl and aryl; wherein the aryl is optionallysubstituted with one to two halogen. Preferably, R⁵ is selected from thegroup consisting of trifluoromethyl and 4-fluorophenyl.

In an embodiment of the present invention, R⁵ is selected from the groupconsisting of methyl, trifluoromethyl, 1,1,2,2,2-pentafluoro-ethyl,—C(O)O-ethyl, 4-methyl-carbonyl-amino-phenyl,4-trifluoromethyl-carbonyl-amino-phenyl and4-methyl-carbonyl-amino-benzyl. In another embodiment of the presentinvention, R⁵ is selected from the group consisting of hydrogen,n-propyl, isopropyl, trifluoromethyl, 4-fluorophenyl,3,4-difluorophenyl, 2,3,4,5,6-pentafluorophenyl, 4-methoxyphenyl,4-ethylphenyl, cyclohexyl, 2-furyl and 2-thienyl.

In an embodiment of the present invention are compounds of formula (I)selected from the group consisting of3-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide;3-Ethyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide;5-(4-Acetylamino-phenyl)-3-methyl-3,4-dihydro-2H-pyrazole-3-carboxylicacid (4-cyano-3-trifluoromethyl-phenyl)-amide;5-(4-Acetylamino-phenyl)-3-methyl-3,4-dihydro-2H-pyrazole-3-carboxylicacid (4-nitro-3-trifluoromethyl-phenyl)-amide;3-Methyl-5-[4-(2,2,2-trifluoro-acetylamino)-phenyl]-3,4-dihydro-2H-pyrazole-3-carboxylicacid (4-nitro-3-trifluoromethyl-phenyl)-amide; and pharmaceuticallyacceptable salts thereof.

In an embodiment of the present invention, the R¹ group on the compoundof formula (I) or the compound of formula (II) is in the (R)stereo-configuration. In another embodiment of the present invention,the R¹ group on the compound of formula (I) or the compound of formula(II) is in the (S) stereo-configuration.

In another embodiment of the present invention is any single compound orsubset of compounds selected from the representative compounds listed inTables 1-4 below.

Additional embodiments of the present invention, include those whereinthe substituents selected for one or more of the variables definedherein (i.e. R¹, R², R³, R⁴, R⁶, R⁷, W, Z, a,

are independently selected to be any individual substituent or anysubset of substituents selected from the complete list as definedherein.

Representative compounds of the present invention are as listed in Table1-9 below. Unless otherwise noted, wherein a stereogenic center ispresent in the listed compound, the compound was prepared as a mixtureof stereo-configurations. Where a stereogenic center is present, the (S)and (R) designations are intended to indicate that the exactstereo-configuration of the center has been determined.

TABLE 1 Representative Compounds of Formula (I)

ID R¹ R³ R⁴ R¹⁰ R⁵ 1 methyl trifluoromethyl cyano H 4-fluoro-phenyl 2methyl trifluoromethyl cyano H 3,4-difluoro-phenyl 3 methyltrifluoromethyl cyano H 4-ethyl-phenyl 4 methyl trifluoromethyl cyano H2-furyl 5 methyl trifluoromethyl cyano benzyl 4-fluoro-phenyl 6 methyltrifluoromethyl nitro H H 7 methyl trifluoromethyl nitro H4-fluoro-phenyl 8 methyl trifluoromethyl cyano H trifluoromethyl 9methyl trifluoromethyl cyano H 2,3,4,5,6- pentafluoro-phenyl 10 methyltrifluoromethyl cyano H 4-methoxy-phenyl 11 methyl trifluoromethyl cyanoH isobutyl 12 methyl trifluoromethyl cyano H 2-fluoro-3-hydroxy- phenyl13 methyl trifluoromethyl chloro H 4-fluoro-phenyl 14 methyltrifluoromethyl cyano H n-propyl 15 methyl trifluoromethyl cyano H ethyl16 methyl H phenyl-carbonyl H H 17 methyl H phenyl-carbonyl Htrifluoromethyl 18 methyl H benzyl H trifluoromethyl 19 methyl Hphenyloxy- H trifluoromethyl 20 methyl H cyano H trifluoromethyl 21methyl H cyano H H 23 methyl trifluoromethyl chloro H trifluoromethyl 24methyl chloro chloro H trifluoromethyl 25 methyl trifluoromethyl cyano Hcyclohexyl 28 methyl H phenyl-thio- H trifluoromethyl 30 ethyltrifluoromethyl cyano H trifluoromethyl 32 methyl H phenyl-sulfonyl Htrifluoromethyl 33 methyl trifluoromethyl cyano H 4-methyl-carbonyl-amino-phenyl 34 methyl trifluoromethyl nitro H 4-methyl-carbonyl-amino-phenyl 35 (S)-methyl trifluoromethyl cyano H trifluoromethyl 36(R)-methyl trifluoromethyl cyano H trifluoromethyl 37 methyltrifluoromethyl nitro H 4-(trifluoro-methyl- carbonyl-amino)- phenyl 38methyl cyano cyano H 4-methyl-carbonyl- amino-phenyl 39 methyltrifluoromethyl cyano methyl 4-methyl-carbonyl- amino-phenyl 40 methyltrifluoromethyl nitro methyl 4-methyl-carbonyl- amino-phenyl 41 methyltrifluoromethyl cyano H 3-methyl-carbonyl- amino-phenyl 42 methyltrifluoromethyl cyano H isopropyl 43 methyl trifluoromethyl cyano H4-methyl-carbonyl- amino-benzyl 44 methyl trifluoromethyl chloro H4-methyl-carbonyl- amino-phenyl 45 methyl trifluoromethyl cyano H4-methoxy- carbonyl-phenyl 46 methyl trifluoromethyl chloro H4-(trifluoro-methyl- carbonyl-amino)- phenyl 47 methyl trifluoromethylcyano H H 48 methyl chloro chloro H H 49 methyl trifluoromethyl cyano H2-thienyl 52 methyl trifluoromethyl cyano H 2-tetrahydro-furyl 56 methyltrifluoromethyl cyano H 3-methyl-4-fluoro- phenyl 57 methyltrifluoromethyl nitro H trimethyl-silyl 73 n-propyl trifluoromethylcyano H trifluoromethyl 74 methyl trifluoromethyl nitro Htrifluoromethyl 75 methyl trifluoromethyl cyano H 2,2,2-trifluoro-ethyl76 methyl trifluoromethyl cyano H 2-hydroxy-phenyl 77 methyltrifluoromethyl cyano H 3-pyridyl 78 methyl trifluoromethyl cyano Hcyclopentyl 79 methyl trifluoromethyl cyano H methyl-thio-ethyl- 81(S)-ethyl trifluoromethyl cyano H trifluoromethyl 82 (R)-ethyltrifluoromethyl cyano H trifluoromethyl 83 methyl trifluoromethyl nitroH ethoxy-carbonyl- 84 methyl trifluoromethyl cyano H ethoxy-carbonyl- 85methyl trifluoromethyl bromo H ethoxy-carbonyl- 86 methyltrifluoromethyl cyano H t-butyl 87 methyl trifluoromethyl cyano Hethyl-thio-ethyl- 89 methyl trifluoromethyl nitro H t-butyl 90 methyltrifluoromethyl cyano H t-butoxy-carbonyl- 91 methyl trifluoromethylcyano H carboxy 92 methyl trifluoromethyl cyano H hydroxy-methyl- 96methyl trifluoromethyl cyano H 2-(t-butyl-dimethyl- silyl)-3-fluoro-phenyl 97 methyl trifluoromethyl cyano H 2-hydroxy-3-fluoro- phenyl 99methyl trifluoromethyl cyano H 1,1,2,2,2- pentafluoro-ethyl 100 methyltrifluoromethyl nitro H 1,1,2,2,2- pentafluoro-ethyl 112 trifluoro-trifluoromethyl cyano H trifluoromethyl methyl 113 trifluoro-trifluoromethyl cyano H ethoxy-carbonyl- methyl 116 trifluoro-trifluoromethyl cyano H methyl methyl 119 methyl trifluoromethyl bromo Htrifluoromethyl 120 methyl trifluoromethyl cyano ethyl trifluoromethyl122 (S)-methyl trifluoromethyl cyano ethyl trifluoromethyl 123 methyltrifluoromethyl cyano methyl trifluoromethyl 125 (R)-methyltrifluoromethyl cyano ethyl trifluoromethyl 131 methyl trifluoromethylcyano tri- trifluoromethyl fluoro- methyl- car- bonyl 135 methyltrifluoromethyl cyano ethyl 4-methyl-carbonyl- amino-phenyl 146 methyltrifluoromethyl cyano ethyl methyl

TABLE 2 Representative Compounds of Formula (I)

ID R¹ R² R³ R⁴ R⁵ 22 methyl H H phenoxy H 26 methyl H H methyl-sulfonyl-H 27 methyl H H methyl-sulfonyl- trifluoromethyl 29 methyl H H chlorotrifluoromethyl 115 methyl trifluoromethyl- trifluoro-methyl cyanotrifluoromethyl carbonyl- 133 methyl methyl trifluoro-methyl cyanotrifluoromethyl

TABLE 3 Representative Compounds of Formula (I)

ID R¹ a R³ R⁴ R⁵ 51 methyl 0 trifluoromethyl cyano trimethyl-silyl 53methyl 0 trifluoromethyl cyano 3,4-difluoro- phenyl 54 methyl 0trifluoromethyl cyano 2-t-butyl- dimethyl- silyloxy- phenyl 55 methyl 0trifluoromethyl cyano 2-hydroxy- phenyl 58 methyl 0 trifluoromethylcyano ethyl 59 methyl 0 trifluoromethyl cyano methyl-thio- ethyl 60methyl 0 trifluoromethyl cyano methyl 61 methyl 0 trifluoromethyl cyanoisobutyl 62 methyl 0 trifluoromethyl cyano n-propyl 63 methyl 0 Hphenyl- trimethyl-silyl carbonyl 64 methyl 0 trifluoromethyl cyano4-fluoro- phenyl 65 methyl 0 H cyano trimethyl-silyl 66 methyl 1 Hphenyloxy- trimethyl-silyl 67 methyl 1 H methyl- trimethyl-silylsulfonyl 68 methyl 0 trifluoromethyl cyano cyclohexyl 69 methyl 0trifluoromethyl cyano isopropyl 98 methyl 0 trifluoromethyl cyano methyl114 methyl 0 trifluoromethyl cyano methyl

TABLE 4 Representative Compounds of Formula (I)

ID

R¹ R³ R⁴ R⁵ 70

methyl trifluoromethyl cyano 4-methyl-carbonyl- amino-phenyl 71

methyl trifluoromethyl nitro 4-methyl-carbonyl amino-phenyl 72

methyl trifluoromethyl cyano 4-methyl-carbonyl amino-phenyl 95

methyl trifluoromethyl cyano 4-fluoro-phenyl 103

methyl trifluoromethyl cyano methyl 104

methyl chloro chloro methyl 105

methyl H cyano methyl 101

methyl trifluoromethyl cyano H 102

methyl trifluoromethyl cyano trifluoro-methyl- carbonyl- 107

methyl trifluoromethyl cyano 4-methyl-carbonyl amino-benzyl 110

methyl trifluoromethyl cyano trifluoromethyl 111

methyl trifluoromethyl cyano absent 124

methyl trifluoromethyl cyano trifluoromethyl 134

methyl trifluoromethyl cyano methyl

TABLE 5 Representative Compounds of formula (I)

ID No.

R⁵ R¹ R² R⁶ R⁷ 126

trifluoromethyl methyl H iodo H 127

trifluoromethyl methyl H H ethyl 128

trifluoromethyl methyl H ethyl H 129

trifluoromethyl methyl H cyano H 130

trifluoromethyl methyl H chloro H 137

trifluoromethyl methyl H chloro chloro 138

trifluoromethyl methyl trifluoro- ethyl chloro chloro 139

trifluoromethyl methyl H chloro chloro 140

trifluoromethyl methyl H ethyl-thio- H 141

trifluoromethyl methyl H methoxy H 142

trifluoromethyl methyl H ethyl- sulfonyl- H 143

trifluoromethyl methyl H t-butyl- thio- H

TABLE 6 Representative Compounds of Formula (I)

ID No.

R⁵ R¹ R² R⁶ R⁷ 147

H methyl H methoxy- carbonyl- H

TABLE 7 Representative Compounds of Formula (I)

ID No.

R⁵ R¹ R³ R⁴ 118

trifluoromethyl methyl trifluoromethyl cyano 136

trifluoromethyl methyl chloro chloro 144

trifluoromethyl (R)- methyl trifluoromethyl cyano 145

trifluoromethyl (S)- methyl trifluoromethyl cyano

TABLE 8 Representative Compounds of Formula (I) ID No Structure 80

88

93

Representative compounds of formula (II) are as listed in Table 9 below.For convenience only one tautomeric form of the compounds listed belowis specifically shown in Table 9.

TABLE 9 Representative Compounds of Formula (II)

ID No.

R¹ R³ R⁴ Z 200

methyl trifluoro- methyl cyano —O-ethyl 201

(S)-methyl trifluoro- methyl cyano —O-ethyl 202

(S)-methyl trifluoro- methyl cyano —O-ethyl 203

methyl trifluoro- methyl cyano —O-methyl 204

methyl trifluoro- methyl cyano —S-ethyl 205

methyl trifluoro- methyl cyano —NH-ethyl 206

methyl trifluoro- methyl cyano —NH—OH 207

methyl trifluoro- methyl cyano —NH₂ 208

methyl trifluoro- methyl cyano —N(ethyl)₂ 209

methyl trifluoro- methyl cyano 1-pyrrolidinyl 210

methyl trifluoro- methyl cyano —NH—O- methyl 211

methyl trifluoro- methyl cyano —NH-methyl 212

methyl trifluoro- methyl cyano —O-methyl 213

methyl chloro chloro —S-ethyl 214

methyl trifluoro- methyl cyano —NH—SO₂- methyl 215

(R)-methyl trifluoro- methyl cyano —S-ethyl 216

(S)-methyl trifluoro- methyl cyano —S-ethyl 217

(S)-methyl trifluoro- methyl cyano —NH-cyano 218

(S)-methyl trifluoro- methyl cyano —S-ethyl

One skilled in the art will recognize that in the recitation of thesubstituent groups of

the “●” symbol is intended to denote the point of attachment of the

ring to the rest of the molecule.

One skilled in the art will further recognize that in the drawing of thesubstituent group

in the compounds of formula (I) and compounds of formula (II), the “C”within the ring structure is intended to indicate a carbon atom. Thuswhen

is other than phenyl, the

ring is attached to the —(CH₂)_(a)— portion of the compounds of formula(I) through a carbon atom. One skilled in the art will further recognizethat the

substituent group further indicates the numbering of the atoms on thering. More specifically, the “C” carbon atom is counted as 1, with theother atoms numbered (counted off) in a clockwise fashion. Thus forexample, wherein the

substituent group is other than phenyl, for example pyridyl, as in thefollowing representative compound of formula (I)

the

substituent group is 3-pyridyl, substituted with a cyano group at the4-position.

As used herein, “halogen” shall mean chlorine, bromine, fluorine andiodine.

As used herein, unless otherwise noted, the abbreviation “C_(a-b)”wherein a and b are integers, is intended to denote the number of carbonatoms within the substituent group. For example, C₁₋₄alkyl denotes alkylchains containing one (1) to four (4) carbon atoms. Similarly,C₂₋₄alkenyl, denotes an alkenyl chain containing two (2) to four (4)carbon atoms.

As used herein, the term “alkyl” whether used alone or as part of asubstituent group, include straight and branched chains. For example,alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, t-butyl, pentyl and the like.

As used herein, unless otherwise noted, the term “halogenated C₁₋₄alkyl”shall mean any straight or branched alkyl chain comprising one to fourcarbon atoms wherein the alkyl chain is substituted with one or more,preferably one to five, more preferably one to three halogen atoms, andwherein the halogen atoms are independently selected from chloro, bromo,fluoro or iodo, preferably chloro or fluoro, more preferably fluoro.Suitable examples include, but are not limited to trifluoromethyl,2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl, and the like.Preferably, the halogenated C₁₋₄alkyl is trifluoromethyl or1-(2,2,2-trifluoroethyl), more preferably, trifluoromethyl.

As used herein, unless otherwise noted, the term “alkenyl” shall includestraight and branched chains comprising at least one unsaturated doublebond. Suitable examples include, but are not limited to, vinyl,1-propenyl, and the like. Preferably, the alkenyl group contains oneunsaturated double bond.

As used herein, unless otherwise noted, “alkoxy” shall denote an oxygenether radical of the above described straight or branched chain alkylgroups. For example, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy,n-hexyloxy and the like.

As used herein, unless otherwise noted, “aryl” shall refer tounsubstituted carbocylic aromatic groups such as phenyl, naphthyl, andthe like.

As used herein, unless otherwise noted, the term “cycloalkyl” shall meanany stable 3-8 membered monocyclic, saturated ring system, for examplecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl andcyclooctyl.

As used herein, unless otherwise noted, “heteroaryl” shall denote anyfive or six membered monocyclic aromatic ring structure containing atleast one heteroatom selected from the group consisting of O, N and S,optionally containing one to three additional heteroatoms independentlyselected from the group consisting of O, N and S; or a nine or tenmembered bicyclic aromatic ring structure containing at least oneheteroatom selected from the group consisting of O, N and S, optionallycontaining one to four additional heteroatoms independently selectedfrom the group consisting of O, N and S. The heteroaryl group may beattached at any heteroatom or carbon atom of the ring such that theresult is a stable structure.

Examples of suitable heteroaryl groups include, but are not limited to,pyrrolyl, furyl, thienyl, oxazolyl, imidazolyl, purazolyl, isoxazolyl,isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl,isoindolinyl, indazolyl, benzofuryl, benzothienyl, benzimidazolyl,benzthiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl,isothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,naphthyridinyl, pteridinyl, and the like.

As used herein, the term “heterocycloalkyl” shall denote any five toseven membered monocyclic, saturated or partially unsaturated ringstructure containing at least one heteroatom selected from the groupconsisting of O, N and S, optionally containing one to three additionalheteroatoms independently selected from the group consisting of O, N andS; or a nine to ten membered saturated, partially unsaturated orpartially aromatic bicyclic ring system containing at least oneheteroatom selected from the group consisting of O, N and S, optionallycontaining one to four additional heteroatoms independently selectedfrom the group consisting of O, N and S. The heterocycloalkyl group maybe attached at any heteroatom or carbon atom of the ring such that theresult is a stable structure.

Examples of suitable heterocycloalkyl groups include, but are notlimited to, pyrrolinyl, pyrrolidinyl, dioxalanyl, imidazolinyl,imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, dioxanyl,morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl,indolinyl, chromenyl, 3,4-methylenedioxyphenyl, 2,3-dihydrobenzofuryl,and the like.

As used herein, unless otherwise noted the term “5 or 6 membered,saturated, heterocyclic ring structure” shall mean any stable ringstructure comprising 5 to 6 ring atoms independently selected from C, N,O and S, wherein the ring structure does not contain any unsaturatedbonds. Preferably, the 5 to 6 membered, saturated heterocyclic ringstructure contains one to two ring atoms selected from the groupconsisting of N, O and S (wherein the remaining ring atoms are C). Morepreferably, the 5 or 6 membered, saturated, heterocyclic ring structurecontains one nitrogen ring atom and optionally contains an additionalring atom selected from the group consisting of O, N and S (wherein theremaining ring atoms are C). Suitable examples include, but are notlimited to pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,pyrazolidinyl, and the like; preferably pyrrolidinyl.

As used herein, the notation “*” shall denote the presence of astereogenic center.

When a particular group is “substituted” (e.g., alkyl, aryl, cycloalkyl,heterocycloalkyl, heteroaryl), that group may have one or moresubstituents, preferably from one to five substituents, more preferablyfrom one to three substituents, most preferably from one to twosubstituents, independently selected from the list of substituents.

With reference to substituents, the term “independently” means that whenmore than one of such substituents is possible, such substituents may bethe same or different from each other.

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including approximations due to the experimental and/or measurementconditions for such given value.

As used herein, unless otherwise noted, the term “aprotic solvent” shallmean any solvent that does not yield a proton. Suitable examplesinclude, but are not limited to DMF, dioxane, THF, acetonitrile,pyridine, dichloroethane, dichloromethane, MTBE, toluene, and the like.

As used herein, unless otherwise noted, the term “leaving group” shallmean a charged or uncharged atom or group which departs during asubstitution or displacement reaction. Suitable examples include, butare not limited to, Br, Cl, I, mesylate, tosylate, and the like.

As used herein, unless otherwise noted, the term “nitrogen protectinggroup” shall mean a group which may be attached to a nitrogen atom toprotect said nitrogen atom from participating in a reaction and whichmay be readily removed following the reaction. Suitable nitrogenprotecting groups include, but are not limited to carbamates—groups ofthe formula —C(O)O—R wherein R is for example methyl, ethyl, t-butyl,benzyl, phenylethyl, CH₂═CH—CH₂—, and the like; amides—groups of theformula —C(O)—R′ wherein R′ is for example methyl, phenyl,trifluoromethyl, and the like; N-sulfonyl derivatives—groups of theformula —SO₂—R″ wherein R″ is for example tolyl, phenyl,trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl-,2,3,6-trimethyl-4-methoxybenzene, and the like. Other suitable nitrogenprotecting groups may be found in texts such as T. W. Greene & P. G. M.Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.

Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.Thus, for example, a “phenylC₁-C₆alkylaminocarbonylC₁-C₆alkyl”substituent refers to a group of the formula

Abbreviations used in the specification, particularly the Schemes andExamples, are as follows:

-   -   Ac=Acetyl (i.e. —C(O)CH₃)    -   AcOH=Acetic acid    -   CDI=N,N′-Carbonyl-Diimidazole    -   CSA=Camphor sulfonic acid    -   DCC=N,N′-Dicyclohexyl-carbodiimide    -   DCM=Dichloromethane    -   DIPEA or DIEA=Diisopropylethylamine    -   DMA N,N-Dimethylacetamide    -   DMF=N,N-Dimethylformamide    -   DMSO=Dimethylsulfoxide    -   EDC=1,2-Dichloroethane    -   Et=Ethyl    -   Et₃N=Triethylamine    -   Et₂O=Diethyl ether    -   EtOAc=Ethyl acetate    -   LiHMDS=Lithium Hexamethyldisilazinamide    -   Me=methyl    -   MeOH=Methanol    -   NCS=N-chlorosuccinimide    -   NMP=1-Methyl-2-pyrrolidinone    -   OXONE®=Potassium monopersulphate triple salt    -   Pd—C or Pd/C=Palladium on Carbon Catalyst    -   PdCl₂(PPh₃)₂=Palladium Bis(triphenylphosphine) chloride    -   PTSA or pTSA=p-Toluene sulfonic acid    -   PyBroP=Bromortri(pyrrolidino)phosphonium hexafluorophosphate    -   TBAF=Tetra(n-butyl)ammonium fluoride    -   TEA=Triethylamine    -   Tf=Triflate    -   TFA=Trifluoroacetic Acid    -   TFAA=Trifluoroacetic acid anhydride    -   THF=Tetrahydrofuran    -   TMS=Trimethylsilyl    -   TMSCHN₂=Trimethylsilyl diazomethane    -   Ts=tosyl (—SO₂— (p-toluene))

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who has been the object of treatment,observation or experiment.

The term “therapeutically effective amount” as used herein, means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thedisease or disorder being treated.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.Preferably, wherein the compound is present as an enantiomer, theenantiomer is present at an enantiomeric excess of greater than or equalto about 80%, more preferably, at an enantiomeric excess of greater thanor equal to about 90%, more preferably still, at an enantiomeric excessof greater than or equal to about 95%, more preferably still, at anenantiomeric excess of greater than or equal to about 98%, mostpreferably, at an enantiomeric excess of greater than or equal to about99%. Similarly, wherein the compound is present as a diastereomer, thediastereomer is present at an diastereomeric excess of greater than orequal to about 80%, more preferably, at an diastereomeric excess ofgreater than or equal to about 90%, more preferably still, at andiastereomeric excess of greater than or equal to about 95%, morepreferably still, at an diastereomeric excess of greater than or equalto about 98%, most preferably, at an diastereomeric excess of greaterthan or equal to about 99%.

Furthermore, some of the crystalline forms for the compounds of thepresent invention may exist as polymorphs and as such are intended to beincluded in the present invention. In addition, some of the compounds ofthe present invention may form solvates with water (i.e., hydrates) orcommon organic solvents, and such solvates are also intended to beencompassed within the scope of this invention.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds which are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound which may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the patient. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

For use in medicine, the salts of the compounds of this invention referto non-toxic “pharmaceutically acceptable salts.” Other salts may,however, be useful in the preparation of compounds according to thisinvention or of their pharmaceutically acceptable salts. Suitablepharmaceutically acceptable salts of the compounds include acid additionsalts which may, for example, be formed by mixing a solution of thecompound with a solution of a pharmaceutically acceptable acid such ashydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinicacid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonicacid or phosphoric acid. Furthermore, where the compounds of theinvention carry an acidic moiety, suitable pharmaceutically acceptablesalts thereof may include alkali metal salts, e.g., sodium or potassiumsalts; alkaline earth metal salts, e.g., calcium or magnesium salts; andsalts formed with suitable organic ligands, e.g., quaternary ammoniumsalts. Thus, representative pharmaceutically acceptable salts includethe following:

acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate,borate, bromide, calcium edentate, camsylate, carbonate, chloride,clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate,esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate,pantothenate, phosphate/diphosphate, polygalacturonate, salicylate,stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate,tosylate, triethiodide and valerate.

Representative acids and bases which may be used in the preparation ofpharmaceutically acceptable salts include the following:

acids including acetic acid, 2,2-dichloroactic acid, acylated aminoacids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid,benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid,(+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonicacid, capric acid, caproic acid, caprylic acid, cinnamic acid, citricacid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid,ethanesulfonic acid, 2-hydrocy-ethanesulfonic acid, formic acid, fumaricacid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconicacid, D-glucoronic acid, L-glutamic acid, α-oxo-glutaric acid, glycolicacid, hipuric acid, hydrobromic acid, hydrochloric acid, (+)-L-lacticacid, (±)-DL-lactic acid, lactobionic acid, maleic acid, (−)-L-malicacid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid,naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid,1-hydroxy-2-naphthoic acid, nicotinc acid, nitric acid, oleic acid,orotic acid, oxalic acid, palmitric acid, pamoic acid, phosphoric acid,L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebaicacid, stearic acid, succinic acid, sulfuric acid, tannic acid,(+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid andundecylenic acid; and bases including ammonia, L-arginine, benethamine,benzathine, calcium hydroxide, choline, deanol, diethanolamine,diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylenediamine,N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesiumhydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassiumhydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodiumhydroxide, triethanolamine, tromethamine and zinc hydroxide.

Compounds of formula (I) wherein

is selected from

may be prepared according to the process outlined in Scheme 1.

Accordingly, a suitably substituted compound of formula (X), a knowncompound or compound prepared by known methods, is reacted with asuitably substituted compound of formula (XI), wherein Q¹ is a suitableleaving group such as hydroxy, halogen, and the like, a known compoundor compound prepared by known methods, according to known methods (forexample, where Q is a halogen, in an organic solvent such as THF,methylene chloride, and the like; where Q is hydroxy, in the presence ofcyanochloride, oxalyl chloride, and the like, in an organic solvent suchas DMA, DMF, and the like), to yield the corresponding compound offormula (XII).

The compound of formula (XII) is reacted with a suitably substituted andprotected hydrazone, a compound of formula (XIII), wherein R⁰ a groupsuch as tolyl, and the like, (wherein —SO₂—R⁰ is a leaving group), aknown compound or compound prepared by known methods, in the presence ofa base such as NaH, potassium t-butoxide, and the like, in an organicsolvent such as THF, dioxane, and the like, at a temperature in therange of from about room temperature to about reflux temperature,preferably at a temperature in the range of from about 80 to about 100°C., to yield the corresponding compound of formula (Ib).

The compound of formula (Ib) is further, optionally converted to thecorresponding compound of formula (Ia) by treating the compound offormula (Ib) with a weak acid such as acetic acid, TFA, dilute HCl, andthe like, or by passing the compound of formula (Ib) through silica gel,according to known methods.

The compound of formula (Ia) is further, optionally reacted with asuitably substituted alkylating agent, according to known methods, toyield the corresponding compound of formula (Ic).

One skilled in the art will recognize that compounds of formula (I)wherein

and wherein R^(5′) is C₁₋₄alkyl may be similarly prepared according tothe process described in Scheme 1 by selecting and substituting asuitably substituted compound of formula (XXXX)

for the compound of formula (XIII) above.

Compounds of formula (I) wherein

and R^(5′) is halogen may be prepared from the corresponding compound offormula (I) wherein

by reacting with a suitable source of the halogen (for example, whereinthe halogen is chloro by reacting with PCl₅ or POCl₃) according to knownmethods.

Compounds of formula (I) wherein

may be similarly prepared according to the process outlined in Scheme 1above, by selecting and substituting a suitably substituted compound offormula (XXXXI)

for the compound of formula (XIII).

Compounds of formula (I) wherein

may be similarly prepared according to the process outlined in Scheme 1above, by selecting and substituting a suitably substituted compound offormula (XXXXII)

for the compound of formula (XIII).

Compounds of formula (Ic) wherein R¹⁰ is other than hydrogen mayalternatively be prepared according to the process outline in Scheme 2.

Accordingly, a suitably substituted compound of formula (XII) is reactedwith a suitably substituted hydrazine, a compound of formula (XIV),wherein X is Cl or Br, a known compound or compound prepared by knownmethods, in the presence of an organic amine base such as TEA, DIPEA,pyridine, and the like, in an organic solvent such as THF, dioxane, andthe like, at a temperature in the range of about 0 to about 50° C.,preferably at about room temperature, to yield the correspondingcompound of formula (Ic).

Compounds of formula (I) wherein

may be prepared according to the process outlined in Scheme 3.

Accordingly, a suitably substituted compound of formula (XII) is reactedwith a suitably substituted compound of formula (XV), wherein X is Cl orBr, a known compound or compound prepared by known methods, in thepresence of an organic amine base such as TEA, DIPEA, pyridine, and thelike, in an organic solvent such as THF, dioxane, and the like, at atemperature in the range of about 0 to about 50° C., preferably at aboutroom temperature, to yield the corresponding compound of formula (Id).

Compounds of formula (I) wherein

may be prepared according to the process outlined in Scheme 4.

Accordingly, a suitably substituted compound of formula (XII) is reactedwith a suitably substituted compound of formula (XVI), a known compoundor compound prepared by known methods, in an organic solvent such astoluene, xylene, chlorobenzene, and the like, at a temperature in therange of about room temperature to about 120° C., to yield thecorresponding compound of formula (Ie).

Compounds of formula (I) wherein may be prepared according to theprocess outlined in Scheme 5.

Accordingly, a suitably substituted compound of formula (XII) is reactedwith a suitable reducing agent such as mCPBA, hydrogen peroxide, and thelike, at a temperature in the range of about 0° C. to about roomtemperature, according to known methods, to yield the correspondingcompound of formula (XVII).

The compound of formula (XVII) is reacted with a suitably substitutedamine, a compound of formula (XVIII), a known compound or compoundprepared by known methods, in an organic solvent such as DMF, DMSO, andthe like, at a temperature in the range of about 0 to about 50° C.,preferably at about room temperature, to yield the correspondingcompound of formula (XIX).

The compound of formula (XIX) is reacted with a suitably substitutedcompound of formula (XX), a known compound or compound prepared by knownmethods, in the presence of an acid such as PTSA, CSA, and the like, inan organic solvent such as toluene, and the like or in an alcohol suchas methanol, ethanol, and the like, at a temperature in the range ofabout 0 to about 50° C., preferably at about room temperature, to yieldthe corresponding compound of formula (If).

Compounds of formula (I) wherein

may be prepared according to the process outlined in Scheme 6.

Accordingly, a suitably substituted compound of formula (XVII) isreacted with a suitably substituted compound of formula (XXI), a knowncompound or compound prepared by known methods, in the presence of aLewis acid such as BF₃● Etherate, AlCl₃, and the like, in an organicsolvent such as methylene chloride, chloroform, and the like, to yieldthe corresponding compound of formula (Ig).

Alternatively, a suitably substituted compound of formula (XlXa), acompound of formula (XIX) wherein R¹⁰ is hydrogen, is reacted with asuitably substituted compound of formula (XXII), wherein Q is a leavinggroup such as hydroxy, halogen, and the like, a known compound orcompound prepared by known methods, according to known methods, at anelevated temperature in the range of from about 50 to about 120° C.,preferably at an elevated temperature in the range of about 80 to about120° C., to yield the corresponding compound of formula (Ig).

Compounds of formula (I) wherein

may be prepared according to the process outlined in Scheme 7.

Accordingly, a suitably substituted compound of formula (XXIII), whereinQ² is suitable leaving group such as OH, halogen, alkoxy,alkyl-carbonyl-oxy-, and the like, is reacted with a suitablysubstituted aldehyde, a compound of formula (XX), a known compound orcompound prepared by known methods, in the presence of an acid such asPTSA, CSA, and the like, in an organic solvent such as toluene, benzene,and the like, at a temperature in the range of from about roomtemperature to about 50° C., to yield the corresponding compound offormula (XXIV).

Wherein the compound of formula (XXIV) Q² is alkoxy and the like, thecompound of formula (XXIV) is reacted with a suitably substitutedcompound of formula (X), a known compound or compound prepared by knownmethods, in the presence of a metallic agent such as (CH₃)₃Al,isopropyl-MgCl, and the like, in an organic solvent such as toluene,THF, and the like, at a temperature in the range of from about 0° C. toabout room temperature, to yield the corresponding compound of formula(Ih).

Alternatively, wherein the compound of formula (XXIV) Q² is hydroxy, thecompound of formula (XXIV) is reacted with a suitably substitutedcompound of formula (X), a known compound or compound prepared by knownmethods, in the presence of a coupling agent such as DCC, EDC, PyBroP,and the like, in the presence of an organic amine such as TEA, DIPEA,pyridine, and the like, in an organic solvent such as DCM, THF, and thelike, at a temperature in the range of from about room temperature toabout 50° C., to yield the corresponding compound of formula (Ih).

Compounds of formula (I) wherein

may be prepared according to the process outlined in Scheme 8.

Accordingly, a suitably substituted compound of formula (XXV), whereinQ³ is a suitable leaving group such as hydroxy, halogen, alkoxy, and thelike, is reacted with 1,1′carbonyl-diimidazole (CDI), in the presence ofan organic amine such as TEA, DIPEA, pyridine, and the like, to yieldthe corresponding compound of formula (XXVI).

Wherein the compound of formula (XXVI) Q³ is alkoxy and the like, thecompound of formula (XXVI) is reacted with a suitably substitutedcompound of formula (X), a known compound or compound prepared by knownmethods, in the presence of a metallic agent such as (CH₃)₃Al,isopropyl-MgCl, and the like, in an organic solvent such as toluene,THF, and the like, at a temperature in the range of from about 0° C. toabout room temperature, to yield the corresponding compound of formula(Ij).

Alternatively, wherein the compound of formula (XXVI) Q³ is hydroxy, thecompound of formula (XXVI) is reacted with a suitably substitutedcompound of formula (X), a known compound or compound prepared by knownmethods, in the presence of a coupling agent such as DCC, EDC, PyBroP,and the like, in the presence of an organic amine such as TEA, DIPEA,pyridine, and the like, in an organic solvent such as DCM, THF, and thelike, at a temperature in the range of from about room temperature toabout 50° C., to yield the corresponding compound of formula (Ij).

Compounds of formula (I) wherein

may be prepared according to the process outlined in Scheme 9.

Accordingly, a suitably substituted compound of formula (XXVII), whereinQ⁴ is a suitable leaving group such as OH, halogen, alkoxy,alkyl-carbonyl-oxy-, and the like, a known compound or compound preparedby known methods, is reacted with a suitably substituted compound offormula (XXVIII), wherein Q⁵ is a suitable leaving group such as OH,halogen, alkoxy, alkyl-carbonyl-oxy-, and the like, a known compound orcompound prepared by known methods, in the presence of a coupling agentsuch as DCC, EDC, PyBroP, and the like, in the presence of an acid suchas PTSA, CSA, and the like, in an organic solvent such as THF, toluene,benzene, and the like, at a temperature in the range of from about 50 toabout 80° C., to yield the corresponding compound of formula (XXIX).

Wherein the compound of formula (XXIX) Q⁴ is alkoxy and the like, thecompound of formula (XXIX) is reacted with a suitably substitutedcompound of formula (X), a known compound or compound prepared by knownmethods, in the presence of a metallic agent such as (CH₃)₃Al,isopropyl-MgCl, and the like, in an organic solvent such as toluene,THF, and the like, at a temperature in the range of from about 0° C. toabout room temperature, to yield the corresponding compound of formula(Ik).

Alternatively, wherein the compound of formula (XXIX) Q⁴ is hydroxy, thecompound of formula (XXIX) is reacted with a suitably substitutedcompound of formula (X), a known compound or compound prepared by knownmethods, in the presence of a coupling agent such as DCC, EDC, PyBroP,and the like, in the presence of an organic amine such as TEA, DIPEA,pyridine, and the like, in an organic solvent such as DCM, THF, and thelike, at a temperature in the range of from about room temperature toabout 50° C., to yield the corresponding compound of formula (Ik).

Compounds of formula (I) wherein

may be prepared according to the process outlined in Scheme 10.

Accordingly, a suitably substituted compound of formula (Im), a compoundof formula (Ic) wherein R⁵ is hydrogen, is reacted with a reducing agentsuch as NaBH₄, NaCNBH₃, and the like, in an organic solvent such asAcOH, CF₃CO₂H, methanol, and the like, at a temperature in the range offrom about 0° C. to about room temperature, to yield the correspondingcompound of formula (In).

The compound of formula (In) is reacted with a suitably substitutedcompound of formula (XXX), wherein Q⁶ is a suitable leaving group suchas halogen, alkyl-carbonyl-oxy-, and the like, in the presence of anorganic amine such as TEA, DIPEA, pyridine, and the like, in an organicsolvent such as DCM, THF, DMF, and the like, at a temperature in therange of from about 0° C. to about room temperature, to yield thecorresponding compound of formula (Ip).

Compounds of formula (I) wherein W is S, may be prepared according tothe process outlined in Scheme 11.

Accordingly, a suitably substituted compound of formula (Ix) is reactedwith a source of sulfur such as Lawesson's reagent, P₂S₅, and the like,in an organic solvent such as toluene, xylene, p-oxlane, and the like,at a temperature in the range of from about 110° C. to about 150° C., toyield the corresponding compound of formula (Iy).

Compounds of formula (II) wherein Q is —OR^(E) may be prepared accordingto the process outlined in Scheme 12.

Accordingly, a suitably substituted compound of formula (Ix) wherein R²is hydrogen, is recated with a suitably substituted electrophile, acompound of formula (XXXI) wherein L^(V) is a suitable leaving groupsuch as Cl, Br, tosyl, triyl, mesyl, and the like, (for example whereR^(E) is ethyl, the compound of formula (XXIX) may be BF₄ etherate), inthe presence of an organic amine base such as TEA, DIPEA, pyridine, andthe like, in an organic solvent such as DCM, THF, diethyl ether, and thelike, at a temperature in the range of from about −40° C. to about roomtemperature, to yield a mixture of the corresponding compound of formula(IIa) and (Iz).

Compounds of formula (II) wherein Q is —SR^(E) or —N(R^(F))₂ may beprepared according to the process outlined in Scheme 13.

Accordingly, a suitably substituted compound of formula (Iy) is reactedwith a suitably substituted compound of formula (XXXI), wherein L^(V) isa suitable leaving group such as Cl, Br, tosyl, trifyl, mesyl, and thelike, a known compound or compound prepared by known methods, in thepresence of an organic amine base such as TEA, DIPEA, pyridine, and thelike, in an organic solvent such as acetone, THF, DMF, and the like, ata temperature in the range of from about 0° C. to about 80° C., to yieldthe corresponding compound of formula (IIb).

The compound of formula (IIb) is reacted with a suitably substitutednitrogen containing nucleophile, a compound of formula (XXXII) (forexample, NH₃, NH(C₁₋₄alkyl), N(C₁₋₄alkyl)₂, NH(OC₁₋₄alkyl), NH₂(OH),NH(CN), NH(SO₂—C₁₋₄alkyl), pyrrolidine, and the like), in the presenceof an inorganic base such as K₂CO₃, NaH, Na₂CO₃, and the like, in anorganic solvent such as THF, DMF, dioxane, and the like, at atemperature in the range of from about room temperature to about 100°C., to yield the corresponding compound of formula (IIc).

One skilled in the art will recognize that when in the compound offormula (IIc) at least one R^(F) group is hydrogen, then thecorresponding compound of formula (I) wherein W is NHR^(F) is itstautomer.

One skilled in the art will recognize that compound of formula (I)wherein

is other than phenyl, may be similarly prepared according to theprocesses outlined in Scheme 1-9 above, by selecting and substitutingsuitably substituted compounds for the starting materials and reagents.

One skilled in the art will recognize that wherein a reaction step ofthe present invention may be carried out in a variety of solvents orsolvent systems, said reaction step may also be carried out in a mixtureof the suitable solvents or solvent systems.

Where the processes for the preparation of the compounds according tothe invention give rise to mixture of stereoisomers, these isomers maybe separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers by standard techniques, such as theformation of diastereomeric pairs by salt formation with an opticallyactive acid, such as (−)-di-p-toluoyl-D-tartaric acid and/or(+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolved byformation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.Alternatively, the compounds may be resolved using a chiral HPLC column.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991. The protectinggroups may be removed at a convenient subsequent stage using methodsknown from the art.

The present invention further comprises pharmaceutical compositionscontaining one or more compounds of formula (I) and/or (II) with apharmaceutically acceptable carrier. Pharmaceutical compositionscontaining one or more of the compounds of the invention describedherein as the active ingredient can be prepared by intimately mixing thecompound or compounds with a pharmaceutical carrier according toconventional pharmaceutical compounding techniques. The carrier may takea wide variety of forms depending upon the desired route ofadministration (e.g., oral, parenteral). Thus for liquid oralpreparations such as suspensions, elixirs and solutions, suitablecarriers and additives include water, glycols, oils, alcohols, flavoringagents, preservatives, stabilizers, coloring agents and the like; forsolid oral preparations, such as powders, capsules and tablets, suitablecarriers and additives include starches, sugars, diluents, granulatingagents, lubricants, binders, disintegrating agents and the like. Solidoral preparations may also be coated with substances such as sugars orbe enteric-coated so as to modulate major site of absorption. Forparenteral administration, the carrier will usually consist of sterilewater and other ingredients may be added to increase solubility orpreservation. Injectable suspensions or solutions may also be preparedutilizing aqueous carriers along with appropriate additives.

To prepare the pharmaceutical compositions of this invention, one ormore compounds of the present invention as the active ingredient isintimately admixed with a pharmaceutical carrier according toconventional pharmaceutical compounding techniques, which carrier maytake a wide variety of forms depending of the form of preparationdesired for administration, e.g., oral or parenteral such asintramuscular. In preparing the compositions in oral dosage form, any ofthe usual pharmaceutical media may be employed. Thus, for liquid oralpreparations, such as for example, suspensions, elixirs and solutions,suitable carriers and additives include water, glycols, oils, alcohols,flavoring agents, preservatives, coloring agents and the like; for solidoral preparations such as, for example, powders, capsules, caplets,gelcaps and tablets, suitable carriers and additives include starches,sugars, diluents, granulating agents, lubricants, binders,disintegrating agents and the like. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit form, in which case solid pharmaceutical carriers areobviously employed. If desired, tablets may be sugar coated or entericcoated by standard techniques. For parenterals, the carrier will usuallycomprise sterile water, through other ingredients, for example, forpurposes such as aiding solubility or for preservation, may be included.Injectable suspensions may also be prepared, in which case appropriateliquid carriers, suspending agents and the like may be employed. Thepharmaceutical compositions herein will contain, per dosage unit, e.g.,tablet, capsule, powder, injection, teaspoonful and the like, an amountof the active ingredient necessary to deliver an effective dose asdescribed above. The pharmaceutical compositions herein will contain,per unit dosage unit, e.g., tablet, capsule, powder, injection,suppository, teaspoonful and the like, of from about 50-100 mg and maybe given at a dosage of from about 0.5-5.0 mg/kg/day, preferably fromabout 1.0-3.0 mg/kg/day. The dosages, however, may be varied dependingupon the requirement of the patients, the severity of the conditionbeing treated and the compound being employed. The use of either dailyadministration or post-periodic dosing may be employed.

Preferably these compositions are in unit dosage forms from such astablets, pills, capsules, powders, granules, sterile parenteralsolutions or suspensions, metered aerosol or liquid sprays, drops,ampoules, autoinjector devices or suppositories; for oral parenteral,intranasal, sublingual or rectal administration, or for administrationby inhalation or insufflation. Alternatively, the composition may bepresented in a form suitable for once-weekly or once-monthlyadministration; for example, an insoluble salt of the active compound,such as the decanoate salt, may be adapted to provide a depotpreparation for intramuscular injection. For preparing solidcompositions such as tablets, the principal active ingredient is mixedwith a pharmaceutical carrier, e.g. conventional tableting ingredientssuch as corn starch, lactose, sucrose, sorbitol, talc, stearic acid,magnesium stearate, dicalcium phosphate or gums, and otherpharmaceutical diluents, e.g. water, to form a solid preformulationcomposition containing a homogeneous mixture of a compound of thepresent invention, or a pharmaceutically acceptable salt thereof. Whenreferring to these preformulation compositions as homogeneous, it ismeant that the active ingredient is dispersed evenly throughout thecomposition so that the composition may be readily subdivided intoequally effective dosage forms such as tablets, pills and capsules. Thissolid preformulation composition is then subdivided into unit dosageforms of the type described above containing from 0.1 to about 500 mg ofthe active ingredient of the present invention. The tablets or pills ofthe novel composition can be coated or otherwise compounded to provide adosage form affording the advantage of prolonged action. For example,the tablet or pill can comprise an inner dosage and an outer dosagecomponent, the latter being in the form of an envelope over the former.The two components can be separated by an enteric layer which serves toresist disintegration in the stomach and permits the inner component topass intact into the duodenum or to be delayed in release. A variety ofmaterial can be used for such enteric layers or coatings, such materialsincluding a number of polymeric acids with such materials as shellac,cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude, aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions, include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

The method of treating a disorder mediated by one or more androgenreceptor(s) described in the present invention may also be carried outusing a pharmaceutical composition comprising any of the compounds asdefined herein and a pharmaceutically acceptable carrier. Thepharmaceutical composition may contain between about 0.1 mg and 500 mg,preferably about 50 to 100 mg, of the compound, and may be constitutedinto any form suitable for the mode of administration selected. Carriersinclude necessary and inert pharmaceutical excipients, including, butnot limited to, binders, suspending agents, lubricants, flavorants,sweeteners, preservatives, dyes, and coatings. Compositions suitable fororal administration include solid forms, such as pills, tablets,caplets, capsules (each including immediate release, timed release andsustained release formulations), granules, and powders, and liquidforms, such as solutions, syrups, elixirs, emulsions, and suspensions.Forms useful for parenteral administration include sterile solutions,emulsions and suspensions.

Advantageously, compounds of the present invention may be administeredin a single daily dose, or the total daily dosage may be administered individed doses of two, three or four times daily. Furthermore, compoundsfor the present invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal skinpatches well known to those of ordinary skill in that art. To beadministered in the form of a transdermal delivery system, the dosageadministration will, of course, be continuous rather than intermittentthroughout the dosage regimen.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders; lubricants, disintegrating agents and coloring agentscan also be incorporated into the mixture. Suitable binders include,without limitation, starch, gelatin, natural sugars such as glucose orbeta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium oleate, sodium stearate, magnesiumstearate, sodium benzoate, sodium acetate, sodium chloride and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum and the like.

The liquid forms in suitably flavored suspending or dispersing agentssuch as the synthetic and natural gums, for example, tragacanth, acacia,methyl-cellulose and the like. For parenteral administration, sterilesuspensions and solutions are desired. Isotonic preparations whichgenerally contain suitable preservatives are employed when intravenousadministration is desired.

The compound of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine or phophatidylcholines.

Compounds of the present invention may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds of the present invention may alsobe coupled with soluble polymers as targetable drug carriers. Suchpolymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidephenol,polyhydroxy-ethylaspartamidephenol, or polyethyl eneoxidepolylysinesubstituted with palmitoyl residue. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyepsilon caprolactone, polyhydroxybutyeric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

Compounds of this invention may be administered in any of the foregoingcompositions and according to dosage regimens established in the artwhenever treatment of disorders mediated by one or more androgenreceptor(s) is required.

The daily dosage of the products may be varied over a wide range from0.01 to 1,000 mg per adult human per day. For oral administration, thecompositions are preferably provided in the form of tablets containing,0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150,200, 250 and 500 milligrams of the active ingredient for the symptomaticadjustment of the dosage to the patient to be treated. An effectiveamount of the drug is ordinarily supplied at a dosage level of fromabout 0.01 mg/kg to about 300 mg/kg of body weight per day. Preferably,the range is from about 0.5 to about 5.0 mg/kg of body weight per day,most preferably, from about 1.0 to about 3.0 mg/kg of body weight perday. The compounds may be administered on a regimen of 1 to 4 times perday.

Optimal dosages to be administered may be readily determined by thoseskilled in the art, and will vary with the particular compound used, themode of administration, the strength of the preparation, the mode ofadministration, and the advancement of the disease condition. Inaddition, factors associated with the particular patient being treated,including patient age, weight, diet and time of administration, willresult in the need to adjust dosages.

The following Examples are set forth to aid in the understanding of theinvention, and are not intended and should not be construed to limit inany way the invention set forth in the claims which follow thereafter.

In the Examples which follow, some synthesis products may be listed ashaving been isolated as a residue. It will be understood by one ofordinary skill in the art that the term “residue” does not limit thephysical state in which the product was isolated and may include, forexample, a solid, an oil, a foam, a gum, a syrup, and the like.

One skilled in the art will recognize that in the Examples which followand describe the preparation of compounds of formula (II) wherein Z isNHR^(F) and their corresponding tautomers (compounds of formula (I)wherein W is NR^(F)), the identity and ratio of the two tautomeric formsin the isolated product was not determined.

EXAMPLE 1 2-Methyl-N-(4-cyano-3-trifluoromethyl-phenyl)-acrylamide

Methyl acrylic acid (510 mg, 6 mmol) in DMA (10 ml) was treated withthionyl chloride (714 mg, 6 mmol) at 0° C. The mixture was stirred for30 min then 4-cyano-3-trifluoromethyl-aniline (1.0 g, 6.0 mmol) wasadded. The resulting suspension was stirred overnight and then quenchedwith NaHCO₃. The reaction mixture was extracted with ethyl acetate,washed with brine and dried with Na₂SO₄. The resulting concentratedcrude product was purified on column (Ethyl acetate:Hexane, 1:2) toyield the title compound as a yellow solid.

¹H NMR (CDCl₃) δ 8.10 (s, 1H), 7.95 (dd, J=1.5 Hz, 0.5 Hz, 1H), 7.90(br, 1H), 7.75 (d, J=1.5 Hz), 5.85 (s, 1H), 5.60 (s, 1H), 2.10 (s, 3H).

MS (m/z): M+Na (277).

EXAMPLE 2 2-Methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-acrylamide

Following the procedure described in Example 1, starting from4-nitro-3-trifluoromethyl-aniline (2.06 g, 10.0 mmol), the titlecompound was prepared as a yellow solid.

¹H NMR (CDCl₃) δ 8.00 (m, 3H), 7.95 (s, 1H), 5.88 (s, 1H), 5.60 (s, 1H),2.10 (s, 3H).

MS (m/z): M+Na (297)

EXAMPLE 3 2-Methyl-N-(4-Chloro-3-trifluoromethyl-phenyl)-acrylamide

Following the procedure described in Example 1, starting from4-chloro-3-trifluoromethyl-aniline, the title compound was prepared as ayellow solid.

¹H NMR (CDCl₃) δ 7.90 (s, 1H), 7.70 (dd, J=1.5 Hz, 0.5 Hz, 1H), 7.40 (d,J=1.5 Hz), 5.80 (s, 1H), 5.50 (s, 1H), 2.00 (s, 3H).

MS (m/z): MH+ (263)

EXAMPLE 4 2-Methyl-N-(4-bromo-3-trifluoromethyl-phenyl)-acrylamide

Following the procedure described in Example 1, starting from4-bromo-3-trifluoromethyl-aniline, the title compound was prepared as ayellow solid.

¹H NMR (CDCl₃) δ 7.90 (s, 1H), 7.85 (s, br, 1H), 7.69 (d, J=7.5 Hz, 1H),7.61 (d, J=7.5 Hz, 1H), 5.85 (s, 1H), 5.55 (s, 1H), 2.08 (s, 3H)

EXAMPLE 5 2-Methyl-N-(3,4-di-chloro-phenyl)-acrylamide

Following the procedure described in Example 1, starting from3,4-di-chloro-aniline, the title compound was prepared as a yellowsolid.

¹H NMR (CDCl₃) δ 7.85 (s, 1H), 7.50 (s, br, 1H), 7.36 (s, 2H), 5.78 (s,1H), 5.51 (s, 1H), 2.08 (s, 3H).

MS (m/z): MH+ (230).

EXAMPLE 6 2-Methyl-N-(3,4-di-cyano-phenyl)-acrylamide

Following the procedure described in Example 1, starting from3,4-di-cyano-aniline the title compound was prepared as a yellow solid.

¹H NMR (CDCl₃) δ 8.25 (s, 1H), 8.05 (s, br, 1H), 7.95 (d, J=7.5 Hz, 1H),7.74 (d, J=7.5 Hz, 1H), 5.88 (s, 1H), 5.65 (s, 1H), 2.11 (s, 3H)

MS (m/z): MNa+ (234)

EXAMPLE 7 N-(4-Benzoyl-phenyl)-2-methyl-acrylamide

Following the procedure described in Example 1, starting from(4-amino-phenyl)-phenyl-methanone, the title compound was prepared as ayellow solid.

¹H NMR (CDCl₃) δ 7.98 (s, br, 1H), 7.88˜7.72 (m, 6H), 7.60 (t, J=8.5 Hz,1H), 7.52 (t, J=7.8 Hz, 2H), 5.88 (s, 1H), 5.55 (s, 1H)

MS (m/z): MH+ (266), MNa+ (288)

EXAMPLE 8 N-(4-Benzoyl-benzyl)-2-methyl-acrylamide

Following the procedure described in Example 1, starting from(4-Aminomethyl-phenyl)-phenyl-methanone, the title compound was preparedas a yellow solid.

¹H NMR (CDCl₃) δ 7.38˜7.22 (m, 4H), 7.10 (t, J=7.5 Hz, 1H), 7.00 (m,4H), 6.15 (s, br, 1H), 5.71 (s, 1H), 5.35 (s, 1H), 4.52 (d, J=4.5 Hz,2H), 2.11 (s, 3H)

MS (m/z): MH+ (280), MNa+ (302)

EXAMPLE 9 2-Methyl-N-(4-phenoxy-phenyl)-acrylamide

Following the procedure described in Example 1, starting from4-phenoxy-phenylamine, the title compound was prepared as a yellowsolid.

¹H NMR (CDCl₃) δ 7.70 (s, 1H), 7.50 (m, 2H), 7.30 (m, 2H), 7.00 (m, 5H),5.80 (s, 1H), 4.90 (s, 1H), 2.00 (s, 3H). MS (m/z): M+1 (254).

MS (m/z): MH+ (254), MNa+ (276)

EXAMPLE 10 2-Methyl-N-(4-cyano-phenyl)-acrylamide

Following the procedure described in Example 1, starting from4-cyano-aniline, the title compound was prepared as a yellow solid.

¹H NMR (CDCl₃) δ 7.70 (m, 5H), 5.80 (s, 1H), 5.05 (s, 1H), 2.00 (s, 3H)

MS (m/z): MH+ (187), MNa+ (209)

EXAMPLE 11 2-Methyl-N-(4-phenylsulfanyl-phenyl)-acrylamide

Following the procedure described in Example 1, starting from4-phenylsulfanyl-phenylamine, the title compound was prepared as ayellow solid.

¹H NMR (CDCl₃) δ 7.60 (s, 1H), 7.55 (d, J=9.0 Hz, 2H), 7.35 (d, J=9.0Hz, 2H), 7.20 (m, 5H), 5.80 (s, 1H), 5.00 (s, 1H), 2.00 (s, 3H)

MS (m/z): MH+ (270), MNa+ (292)

EXAMPLE 12 N-(4-Benzyl-phenyl)-2-methyl-acrylamide

Following the procedure described in Example 1, starting from4-benzyl-phenylamine, the title compound was prepared as a yellow solid.

¹H NMR (CDCl₃) δ 8.00 (d, J=9.0 Hz, 1H), 7.15-7.35 (m, 9H), 5.35 (s,1H), 5.25 (s, 1H), 1.75 (s, 3H)

MS (m/z): MH+ (252), MNa+ (274)

EXAMPLE 13 N-(4-Methanesulfonyl-benzyl)-2-methyl-acrylamide

Following the procedure described in Example 1, starting from4-methanesulfonyl-benzylamine, the title compound was prepared as ayellow solid.

¹H NMR (CDCl₃) δ 7.75 (d, J=8.5 Hz, 2H), 7.42 (d, J=8.5 Hz, 2H), 6.92(s, 1H), 5.78 (s, 1H), 5.38 (s, 1H), 4.55 (d, J=6.5 Hz, 2H), 3.02 (s,3H), 2.05 (s, 3H)

MS (m/z): MH+ (254), MNa+ (276)

EXAMPLE 14 N-(4-Chloro-benzyl)-2-methyl-acrylamide

Following the procedure described in Example 1, starting from4-chloro-benzylamine, the title compound was prepared as a yellow solid.

¹H NMR (CDCl₃) δ 7.20 (m, 4H), 6.15 (s, 1H), 5.75 (s, 1H), 4.85 (s, 1H),4.50 (d, J=5.0 Hz, 2H), 2.00 (s, 3H).

MS (m/z): MH+ (210).

EXAMPLE 15 N-(4-phenoxy-benzyl)-2-methyl-acrylamide

Following the procedure described in Example 1, starting from4-phenoxy-benzylamine, the title compound was prepared as a yellowsolid.

¹H NMR (CDCl₃) δ 7.18˜6.94 (m, 4H), 6.85 (t, J=6.5 Hz, 1H), 6.77 (m,4H), 5.56 (s, br, 1H), 5.65 (s, 1H), 5.30 (s, 1H), 4.38 (d, J=5.5 Hz,2H), 2.06 (s, 3H)

MS (m/z): MH+ (268), MNa+ (290)

EXAMPLE 16 N-(4-Cyano-3-trifluoromethyl-phenyl)-2-ethyl-acrylamide

Following the procedure described in Example 1, starting from4-cyano-3-trifluoromethyl-aniline and 2-ethyl-acrylic acid, the titlecompound was prepared as a yellow solid.

¹H NMR (CDCl₃) δ 8.70 (s, 1H), 8.18 (s, 1H), 8.06 (d, J=12.0H, 1H), 7.78(d, J=12.0 Hz, 1H), 5.75 (s, 1H), 5.05 (s, 1H), 2.40 (q, J=9.0 Hz, 2H),1.11 (t, J=9.0 Hz, 3H).

MS (m/z): MH+ (270), MNa+ (292)

EXAMPLE 17 N-(4-Cyano-3-trifluoromethyl-phenyl)-2-propyl-acrylamide

Following the procedure described in Example 1, starting from4-cyano-3-trifluoromethyl-aniline and 2-propyl-acrylic acid, the titlecompound was prepared as a yellow solid.

MS (m/z): MH+ (284), MNa+ (306).

¹H NMR (CDCl₃) δ 8.20 (s, 1H), 8.12 (s, 1H), 8.00 (d, J=12.0 Hz, 1H),7.78 (d, J=12.0 Hz, 1H), 5.70 (s, 1H), 5.00 (s, 1H), 2.40 (t, J=9.0 Hz,2H), 1.50 (m, 2H), 0.95 (t, J=9.0 Hz, 3H).

EXAMPLE 18 N-Benzyl-N″-(4-fluoro-benzylidene)-hydrazine

4-Fluorobenzenealdehyde (1.24 g, 10.0 mmol) in benzene (40 ml) was mixedwith benzyl hydrazine hydrochloride (1.95 g, 10.0 mmol). The reactionwas stirred at room temperature for 12 h. The solvent was then removedby vacuum evaporation to yield the title compound as a white solid.

¹H NMR (CDCl₃) δ 7.60 (m, 2H), 7.30 (m, 5H), 7.05 (m, 2H), 4.45 (s, 1H).

MS (m/z): MH+ (227)

EXAMPLE 19 N-[4-(Methyl-hydrazonomethyl)-phenyl]-acetamide

Following the procedure described in Example 18, starting fromN-(4-formyl-phenyl)-acetamide and methyl hydrazine, the title compoundwas prepared as a white solid.

EXAMPLE 20 4-Fluoro-benzaldehyde oxime

Following the procedure described in Example 18, starting fromN-(4-formyl-phenyl)-acetamide and N-hydroxyamine, the title compound wasprepared as a white solid.

MS (m/z): MH+ (140).

EXAMPLE 21 4-Fluoro-N-(phenylmethyl)-benzenecarbohydrazonoyl chloride

NCS (1.33 g, 10.0 mmol) was mixed with dimethyl sulfide (620 mg, 10.0mmol) in CH₂Cl₂ (20 ml) at 0° C. for 30 min. The mixture was then cooledto −78° C. and N-benzyl-N″-(4-fluoro-benzylidene)-hydrazine, prepared asin Example 19, (2.62 g, 10.0 mmol) was added into the mixture. Themixture was maintained at −78° C. for 1 h, then slowly warmed up to roomtemperature over 2 hrs. The reaction mixture was quenched by NaHCO₃,then extracted with ethyl acetate. The organic layer was combined,washed with brine, dried over Na₂SO₄ and concentrated to yield a crudeproduct. Purification of the crude product on column (100% CH₂Cl₂,Rf=0.5) yielded the title compound as a white solid.

¹H NMR (CDCl₃) δ 7.80 (m, 2H), 7.30 (m, 5H), 7.05 (m, 2H), 6.10 (br,1H).

MS (m/z): MH+ (260).

EXAMPLE 22 4-acetamido-N-(methyl)-benzenecarbohydrazonoyl chloride

Following the procedure described in Example 21, starting fromN-[4-(methyl-hydrazonomethyl)-phenyl]-acetamide, the title compound wasprepared as a white solid.

MS (m/z): MH+ (226).

EXAMPLE 232-Benzyl-5-(4-fluoro-phenyl)-3-methyl-3,4-dihydro-2H-pyrazole-3-carboxylicacid (4-cyano-3-trifluoromethyl-phenyl)-amide Compound #5

N-(4-Cyano-3-trifluoromethyl-phenyl)-2-methyl-acrylamide (500 mg, 2.0mmol) was mixed with 4-fluoro-N-(phenylmethyl)-benzenecarbohydrazonoylchloride (520 mg, 2.0 mmol) in CH₂Cl₂ at room temperature. Triethylamine (300 mg, 3.0 mmol) was then added to the reaction mixture. Thereaction was refluxed overnight, then quenched with NaHCO₃, andextracted with ethyl acetate. The organic layer was combined, washedwith brine, dried over Na₂SO₄ and concentrated to yield a crude product.Purification of the crude product on column (Hexane:ethyl acetate, 5:1,Rf=0.5) yielded the title compound as a white solid.

¹H NMR (CDCl₃) δ 9.25 (s, 1H), 7.80 (s, 1H), 7.70 (s, 2H), 7.60 (m, 2H),7.45 (m, 2H), 7.05 (m, 5H), 4.30 (dd, J=11.1 Hz, 1.0 Hz, 2H), 3.30 (dd,J=3.6 Hz, 1.2 Hz, 2H), 1.65 (s, 3H).

MS (m/z): MH+ (481)

EXAMPLE 245-(4-Fluoro-phenyl)-3-methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide Compound #1

2-Benzyl-5-(4-fluoro-phenyl)-3-methyl-3,4-dihydro-2H-pyrazole-3-carboxylicacid (4-cyano-3-trifluoromethyl-phenyl)-amide (150 mg, 0.33 mmol) inethanol, was treated with Pd/C (100 mg, 10%) under H₂ balloon for twodays. Pd/C was removed by vacuum filtration and the solvent was removedby vacuum rotary evaporation to yield a crude product. Purification ofthe crude product by silica gel (Hex:ethyl acetate, 2:1, Rf=0.4) yieldedthe title compound as a white solid.

¹H NMR (CDCl₃) δ 9.75 (s, 1H), 8.10 (s, 1H), 7.85 (dd, J=4.5 Hz, 0.2 Hz,2H), 7.65 (m, 2H), 7.05 (m, 2H), 5.70 (br, 1H), 3.30 (dd, J=3.6 Hz, 1.2Hz, 2H), 1.65 (s, 3H)

MS (m/z): MH+ (390)

EXAMPLE 255-(4-Acetylamino-phenyl)-2,3-dimethyl-3,4-dihydro-2H-pyrazole-3-carboxylicacid (4-cyano-3-trifluoromethyl-phenyl)-amide Compound #39

Following the procedure described in Example 23, starting from2-methyl-N-(4-cyano-3-trifluoromethyl-phenyl)-acrylamide and4-acetamido-N-(methyl)-benzenecarbohydrazonoyl chloride, the titlecompound was prepared as a white solid.

¹H NMR (CDCl₃) δ 9.62 (s, 1H), 8.18 (s, 1H), 8.02 (d, J=7.5 Hz, 1H),7.98 (d, J=7.5 Hz, 1H), 7.80 (s, 1H), 7.50 (m, 4H), 3.38 (abq, J=12.5Hz, 2H), 2.98 (s, 3H), 2.20 (s, 3H), 1.50 (s, 3H).

MS (m/z): MH+ (444), MH− (442)

EXAMPLE 265-(4-Acetylamino-phenyl)-2,3-dimethyl-3,4-dihydro-2H-pyrazole-3-carboxylicacid (4-nitro-3-trifluoromethyl-phenyl)-amide Compound #40

Following the procedure described in Example 23, starting from2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-acrylamide and4-acetamido-N-(methyl)-benzenecarbohydrazonoyl chloride, the titlecompound was prepared as a white solid.

¹H NMR (CDCl₃) δ 9.52 (s, 1H), 8.15 (s, 1H), 8.06 (d, J=7.5 Hz, 1H),7.95 (d, J=7.5 Hz, 1H), 7.61 (s, 1H), 7.55 (m, 4H), 3.38 (abq, J=12.5Hz, 2H), 2.98 (s, 3H), 2.18 (s, 3H), 1.48 (s, 3H)

MS (m/z): MH+ (464), MNa+ (486)

EXAMPLE 273-(4-Fluoro-phenyl)-5-methyl-4,5-dihydro-isoxazole-5-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide Compound #95

4-Fluorobenzamidoxime (1.39 g, 10 mmol) was mixed with triethylamine(200 mg, 2.0 mmol) and NaOCl (4%, 15 ml, 1.48 g, 10 mmol) in CH₂Cl₂ (25ml). N-(4-(Cyano-3-trifluoromethyl-phenyl)-2-methyl-acrylamide (508 mg,2.0 mmol) was added into the mixture and the mixture was then stirredfor 3 hrs at room temperature. The reaction mixture was quenched byNaHCO₃, and then extracted with ethyl acetate. The organic layer wascombined, washed with brine, dried over Na₂SO₄ and concentrated to yielda crude product. Purification of the crude product on column(Hexane:ethyl acetate, 2:1, Rf=0.45) yielded the title compound as awhite solid.

¹H NMR (CDCl₃) δ 9.15 (s, 1H), 8.15 (s, 1H), 7.85 (dd, J=4.5 Hz, 0.2 Hz,2H), 7.60 (m, 2H), 7.05 (m, 2H), 3.75 (dd, J=17.4 Hz, 2.0 Hz, 2H), 1.75(s, 3H).

MS (m/z): MH+ (392)

EXAMPLE 28 1-R-p-Toluenesulfonylhydrazone (General procedure)

p-Toluenesulfonylhydrazine (10.0 mmol) was mixed with a suitablyselected compound of the formula R—CHO (10.0 mmoL) in methanol (40 ml)at room temperature for 4 h. The mixture was then concentrated to yieldthe title compound as a white solid (unless otherwise noted).

EXAMPLE 295-(4-Fluoro-phenyl)-3-methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide and5-(4-Fluoro-phenyl)-3-methyl-4,5-dihydro-3H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide Compound #1 and Compound #64

2-[(1E)-(4-fluorophenyl)methylidene]toluenesulfonylhydrazone, preparedaccording to the procedure described in Example 29 (600 mg, 2.1 mmol) inTHF (20 ml) was treated by NaH (60%, 120 mg, 3 mmol) at 0° C. for 20min, followed by the addition ofN-(4-cyano-3-trifluoromethyl-phenyl)-2-methyl-acrylamide (500 mg, 2.0mmol). The reaction mixture was then heated to 55° C. overnight, thenquenched by NaHCO₃, and extracted by ethyl acetate. The organic layerwas combined, washed with brine, dried over Na₂SO₄ and concentrated toyield crude product as a mixture. Purification of the crude product on acolumn yielded the title compound as separate products, as a whitesolids.

5-(4-Fluoro-phenyl)-3-methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide

(Hexane:ethyl acetate, 2:1, Rf=0.45, 475 mg, 61%)

5-(4-Fluoro-phenyl)-3-methyl-4,5-dihydro-3H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide

(Hexane:ethyl acetate: 2:1, Rf=0.6, 100 mg, 13%):

MS (m/z): MH+ (391)

¹H NMR (CDCl₃) δ 8.50 (s, 1H), 8.10 (s, 1H), 7.90 (dd, J=1.5 Hz, 0.2 Hz,1H), 7.75 (d, J=1.5 Hz, 1H), 7.20 (m, 2H), 7.10 (m, 2H), 5.60 (t, J=0.9Hz, 1H), 3.00 (dd, J=1.0 Hz, 0.8 Hz, 1H), 1.87 (s, 3H), 1.55 (t, J=1.1Hz, 0.6 Hz, 1H).

EXAMPLE 305-(4-Fluoro-phenyl)-3-methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-nitro-3-trifluoromethyl-phenyl)-amide Compound #7

Following the procedure described in Example 29, starting from2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-acrylamide and2-[(1E)-(4-fluorophenyl)methylidene]toluenesulfonylhydrazone, the titlecompound was prepared as a yellow solid.

¹H NMR (MeOH) δ 6.45 (d, J=0.9 Hz, 1H), 6.20 (m, 1H), 6.00 (s, 1H), 5.55(m, 4H), 2.00 (dd, J=5.5 Hz, 1.8 Hz, 2H), 1.70 (s, 3H).

MS (m/z): MNa+ (410)

EXAMPLE 313-Methyl-5-trimethylsilanyl-4,5-dihydro-3H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide and3-Methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide Compound #51 and Compound #47

N-(4-Cyano-3-trifluoromethyl-phenyl)-2-methyl-acrylamide (180 mg, 0.71mmoL) in THF (5 mL) was treated with TMSCHN₂ (2.0 M in hexanes, 3.54mmoL, 1.8 mL) at −10° C. The reaction mixture was then warmed to roomtemperature slowly and stirred overnight. The solvent was removed andthe residue was purified by column chromatography (silica gel, 1:1hexanes:EtOAc) to yield the title compound as a white solids (1:1diastereomers).

3-Methyl-5-trimethylsilanyl-4,5-dihydro-3H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide

¹H NMR (CDCl₃) δ 8.58 (br, s, 1H) for diastereomer 1, 8.35 (br, s, 1H)for diastereomer 2, 7.90 (m, 1), 7.70 (m, 1H), 7.58 (m, 1H), 4.35 (dd,J=10.5, 5.0 Hz, 1H) for diastereomer 1, 4.30 (dd, J=11.0, 6.0 Hz, 1H)for diastereomer 2, 2.30 (m, 1H) for diastereomer 1, 2.05 (m, 1H) fordiastereomer 2, 1.66 (m, 1H) for diastereomer 1, 1.48 (s, 3H) fordiastereomer 1, 1.42 (s, 3H) for diastereomer 2, 1.29 (m, 1H) fordiastereomer 2), 0.10 (s, 9H) for diastereomer 1), 0.01 (s, 9H) fordiastereomer 2

MS (m/z), 298 [M-TMS+H]⁺, 319 [M-TMS+Na]⁺

3-Methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide

¹H NMR (CDCl₃) 9.62 (s, 1H), 8.10 (s, 1H), 7.95 (d, J=6.5 Hz, 1H), 7.77(d, J=6.5 Hz, 1H), 6.88 (s, 1H), 5.52 (s, 1H), 3.05 (abq, J=12.5 Hz,2H), 1.56 (s, 3H)

MS (m/z), MH+ (297).

EXAMPLE 32 3-Methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-nitro-3-trifluoromethyl-phenyl)-amide and3-Methyl-5-trimethylsilanyl-4,5-dihydro-3H-pyrazole-3-carboxylic acid(4-nitro-3-trifluoromethyl-phenyl)-amide Compound #6 and Compound #57

Following the procedure described in Example 31, starting from2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-acrylamide and TMSCHN₂ thetitle compounds were prepared, both as a white solids.

3-Methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-nitro-3-trifluoromethyl-phenyl)-amide

¹H NMR (CDCl₃) δ 9.62 (br, s, 1H), 8.10 (s, 1H), 7.98 (m, 2H), 6.88 (s,1H), 5.50 (s, 1H), 3.10 (Abq, J=12.5 Hz, 2H), 1.52 (s, 3H)

MS (m/z), MH⁺, 317, MH⁻, 315

3-Methyl-5-trimethylsilanyl-4,5-dihydro-3H-pyrazole-3-carboxylic acid(4-nitro-3-trifluoromethyl-phenyl)-amide

¹H NMR (CDCl₃) δ 8.78 (br, s, 1H), 8.05 (s, 1H), 7.88 (d, J=7.0 Hz, 1H),7.74 (d, J=7.0 Hz, 1H), 4.48 (dd, J=11.0, 4.5 Hz, 1H), 2.10 (dd, J=13.0,11.0 Hz, 1H), 1.78 (dd, J=13.0, 4.5 Hz, 1H), 1.55 (s, 3H)

EXAMPLE 33N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]phenyl]-4,5-dihydro-5-methyl-1H-pyrazole-5-carboxamideCompound #54

Following the procedure described in Example 29,4-methyl-2-[(1Z)-[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]phenyl]methylidene]benzenesulfonylhydrazone was reacted to yield the title compound as a white solid.

¹H NMR (CDCl₃) δ 9.25 (s, 1H), 8.16 (s, 1H), 7.95 (d, J=0.6 Hz, 1H),7.65 (d, J=0.6 Hz, 1H), 7.10 (m, 1H), 6.80 (m, 3H), 5.80 (m, 1H), 2.30(m, 1H), 1.80 (m, 1H), 1.51 (s, 3H), 0.89 (s, 9H), 0.21 (s, 6H)

MS (m/z): M+(503)

EXAMPLE 34N-[4-cyano-3-(trifluoromethyl)phenyl]-4,5-dihydro-3-(2-hydroxyphenyl)-5-methyl-1H-pyrazole-5-carboxamideand 5-(2-hydroxy-phenyl)-3-methyl-4,5-dihydro-3H-pyrazole-3-carboxylicacid (4-cyano-3-trifluoromethyl-phenyl)-amide Compound #76 and Compound#55

N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]phenyl]-4,5-dihydro-5-methyl-1H-pyrazole-5-carboxamide,prepared as in Example 34 (80 mg, 1.6 mmol) in THF (20 ml) was treatedwith TBAF (1M, 3.2 ml, 3.2 mmol) at 0° C. The reaction mixture wasstirred at room temperature for 2 h, then quenched with H₂O, extractedwith ethyl acetate, dried over Na₂SO₄ and concentrated to yield a crudeproduct. The crude product was purified by silica gel (Hexane:ethylacetate, 2:1, Rf=0.35) to yield the title compound as a white solid.

N-[4-cyano-3-(trifluoromethyl)phenyl]-4,5-dihydro-3-(2-hydroxyphenyl)-5-methyl-1H-pyrazole-5-carboxamide

¹H NMR (CDCl₃) δ10.78 (br, 1H), 9.75 (s, 1H), 8.16 (s, 1H), 7.95 (d,J=0.6 Hz, 1H), 7.70 (d, J=0.6 Hz, 1H), 7.25 (m, 1H), 7.08 (d, J=0.6 Hz,1H), 6.85 (m, 1H), 5.95 (s, 1H), 3.40 (dd, J=5.1 Hz, 2.1 Hz, 1H), 1.65(s, 3H)

MS (m/z): MNa+ (401)

5-(2-hydroxy-phenyl)-3-methyl-4,5-dihydro-3H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide

¹H NMR (CDCl₃) δ 9.80 (s, 1H), 8.25 (s, 1H), 7.90 (d, J=7.6 Hz, 1H),7.70 (d, J=7.6 Hz, 1H), 7.65 (s, 1H), 7.55 (d, J=6.6 Hz, 2H), 6.92 (d,J=6.6 Hz, 2H), 5.70 (br, 1H), 3.15 (abq, J=12.5 Hz, 1H), 1.55 (s, 3H)

MS (m/z): MNa+ (401)

EXAMPLE 35N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3-fluorophenyl]-4,5-dihydro-5-methyl-1H-pyrazole-5-carboxamideCompound #96

Following the procedure described in Example 29,4-methyl-2-[(1Z)-[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3-fluorophenyl]methylidene]benzenesulfonylhydrazone was reacted to yield the title compound as a white solid.

¹H NMR (CDCl₃) δ 9.60 (s, 1H), 8.00 (s, 1H), 7.78 (d, J=0.6 Hz, 1H),7.65 (d, J=0.6 Hz, 1H), 7.10 (m, 1H), 6.95 (m, 1H), 6.75 (m, 1H), 5.50(br, 1H), 3.25 (dd, J=5.1 Hz 1.2 Hz, 2H), 1.55 (s, 3H), 0.78 (s, 9H),0.21 (d, J=4.8 Hz, 6H)

MS (m/z): M Na+ (544), M− (520)

EXAMPLE 36N-[4-cyano-3-(trifluoromethyl)phenyl]-3-(3-fluoro-2-hydroxyphenyl)-4,5-dihydro-5-methyl-1H-pyrazole-5-carboxamideCompound #97

Following the procedure described in Example 34,N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3-fluorophenyl]-4,5-dihydro-5-methyl-1H-pyrazole-5-carboxamide,prepared as in Example 36, was reacted to yield the title compound as awhite solid.

MS (m/z): M+ (407)

¹H NMR (CDCl₃) δ10.84 (s, 1H), 9.63 (s, 1H), 8.14 (s, 1H), 7.97 (d,J=0.6 Hz, 1H), 7.79 (d, J=0.6 Hz, 1H), 7.11 (m, 1H), 6.92 (m, 1H), 6.82(m, 1H), 5.87 (s, 1H), 3.45 (dd, J=3.6 Hz, 1.2 Hz, 2H), 1.69 (s, 3H)

EXAMPLE 37 3-Methyl-5-thiophen-2-yl-3,4-dihydro-2H-pyrazole-3- arboxylicacid (4-cyano-3-trifluoromethyl-phenyl)-amide Compound #49

Following the procedure described in Example 29,4-methyl-2-[(1E)-2-thienylmethylidene]benzenesulfonyl hydrazone wasreacted to yield the title compound as a white solid.

¹H NMR (CDCl₃) δ 9.75 (s, 1H), 8.13 (s, 1H), 7.92 (dd, J=1.1 Hz, 0.2 Hz,1H), 7.78 (d, J=0.8 Hz, 1H), 7.37 (m, 1H), 7.11 (m, 1H), 7.04 (m, 1H),5.55 (br, 1H), 3.35 (dd, J=5.4 Hz, 1.7 Hz, 2H), 1.65 (s, 3H)

MS (m/z): MH+ (379)

EXAMPLE 38 5-Furan-2-yl-3-methyl-4,5-dihydro-3H-pyrazole-3- arboxylicacid (4-cyano-3-trifluoromethyl-phenyl)-amide Compound #4

Following the procedure described in Example 29,4-methyl-2-[(1E)-2-furanylmethylidene]benzenesulfonyl hydrazone wasreacted to yield the title compound as a white solid.

¹H NMR (CDCl₃) δ 9.75 (s, 1H), 8.13 (s, 1H), 7.92 (dd, J=1.1 Hz, 0.2 Hz,1H), 7.78 (d, J=0.8 Hz, 1H), 6.65-6.50 (m, 3H), 3.31 (dd, J=5.4 Hz, 1.7Hz, 2H), 1.65 (s, 3H)

MS (m/z): MH+ (363)

EXAMPLE 393-Methyl-5-(tetrahydro-furan-2-yl)-4,5-dihydro-3H-pyrazole-3-carboxylicacid (4-cyano-3-trifluoromethyl-phenyl)-amide Compound #52

Following the procedure described in Example 29,4-methyl-2-[(1E)-(tetrahydro-2-furanyl)methylidene]benzenesulfonylhydrazone was reacted to yield the title compound as a white solid.

¹H NMR (CDCl₃) δ 9.09 (s, 1H), 8.16 (m, 1H), 7.95 (m, 1H), 7.81 (d,J=0.6 Hz, 1H), 4.49 (dd, J=1.0 Hz, 0.5 Hz, 1H), 4.00-3.60 (m, 3H),2.50-1.60 (m, 6H), 1.56 (s, 3H)

MS (m/z): MH+ (366)

EXAMPLE 403-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide Compound #8

Following the procedure described in Example 29,4-methyl-2-[(1E)-2,2,2-trifluoroethylidene]benzenesulfonyl hydrazone wasreacted to yield the title compound as a white solid.

¹H NMR (CDCl₃) δ 9.30 (s, 1H), 8.11 (s, 1H), 7.98 (dd, J=1.1 Hz, 0.2 Hz,1H), 7.80 (d, J=0.8 Hz, 1H), 6.18 (br, 1H), 3.15 (dd, J=6.0 Hz, 1.8 Hz,2 H), 1.62 (s, 3H)

MS (m/z): MNa+ (387)

EXAMPLE 41 5-Cyclohexyl-3-methyl-3,4-dihydro-2H-pyrazole-3-carboxylicacid (4-cyano-3-trifluoromethyl-phenyl)-amide and5-Cyclohexyl-3-methyl-4,5-dihydro-3H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide Compound #25 and Compound #68

Following the procedure described in Example 29,4-methyl-2-[(1E)-cyclohexylmethylidene]benzenesulfonyl hydrazone wasreacted to yield the two title compounds as a white solids.

5-Cyclohexyl-3-methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide

(Hexane:Ethyl Acetate, 2:1, Rf=0.2, 210 Mg, 19%)

¹H NMR (CDCl₃) δ 9.82 (s, 1H), 8.10 (s, 1H), 7.95 (dd, J=1.0 Hz, 0.2 Hz,1H), 7.78 (d, J=0.8 Hz, 1H), 2.98 (dd, J=5.1 Hz, 1.7 Hz, 2H), 1.77 (m,6H), 1.50 (s, 3H), 1.27 (m, 4H).

MS (m/z): MH+ (379)

5-Cyclohexyl-3-methyl-4,5-dihydro-3H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide

(Hexane:Ethyl Acetate, 2:1, Rf=0.8, 160 Mg, 16%)

¹H NMR (CDCl₃) δ 9.20 (s, 1H), 8.20 (s, 1H), 8.05 (dd, J=1.0 Hz, 0.2 Hz,1H), 7.85 (d, J=0.9 Hz, 1H), 4.36 (dd, J=1.5 Hz, 0.8 Hz, 1H), 2.15 (d,J=1.0 Hz, 1H), 1.70 (m, 6H), 1.55 (s, 3H), 1.20 (m, 5H)

MS (m/z): MNa+ (401)

EXAMPLE 425-(4-Ethyl-phenyl)-3-methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide Compound #3

Following the procedure described in Example 29,4-methyl-2-[(1E)-(4-ethylphenyl)methylidene]benzenesulfonyl hydrazonewas reacted to yield the title compound as a white solid.

¹H NMR (CDCl₃) δ 9.80 (s, 1H), 8.16 (m, 1H), 7.90 (d, J=0.6 Hz, 1H),7.78 (d, J=0.6 Hz, 1H), 7.50 (d, J=0.8 Hz, 2H), 7.15 (d, J=0.8 Hz, 2H),5.83 (br, 1H), 3.32 (dd, J=3.9 Hz, 1.3 Hz, 1H), 2.65 (q, J=0.6 Hz, 2H),1.62 (s, 3H), 1.20 (t, J=0.4 Hz, 3H)

MS (m/z): MH+ (401)

EXAMPLE 435-(4-Fluoro-3-methyl-phenyl)-3-methyl-3,4-dihydro-2H-pyrazole-3-carboxylicacid (4-cyano-3-trifluoromethyl-phenyl)-amide Compound #56

Following the procedure described in Example 29,4-methyl-2-[(1E)-(4-fluoro-3-methylphenyl)methylidene]benzenesulfonylhydrazone was reacted to yield the title compound as a white solid.

¹H NMR (CDCl₃) δ 9.75 (s, 1H), 8.16 (s, 1H), 7.95 (d, J=0.6 Hz, 1H),7.78 (d, J=0.6 Hz, 1H), 7.50-7.40 (m, 2H), 7.05 (m, 2H), 4.60 (br, 1H),3.30 (dd, J=3.9 Hz, 1.3 Hz, 1H), 2.30 (s, 3H), 1.65 (s, 3H)

MS (m/z): MNa+ (427)

EXAMPLE 44 5-Isopropyl-3-methyl-3,4-dihydro-2H-pyrazole-3-carboxylicacid (4-cyano-3-trifluoromethyl-phenyl)-amide and5-Isopropyl-3-methyl-4,5-dihydro-3H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide Compound #42 and Compound #69

Following the procedure described in Example 29,4-methyl-2-[(1E)-2-methylpropylidene]benzenesulfonyl hydrazone wasreacted to yield the two title compounds as a white solids.

5-Isopropyl-3-methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide

(Hexane:Ethyl Acetate, 2:1, Rf=0.2, 350 Mg, 35%)

¹H NMR (CDCl₃) δ 9.85 (s, 1H), 8.10 (s, 1H), 7.95 (dd, J=1.0 Hz, 0.2 Hz,1H), 7.78 (d, J=0.8 Hz, 1H), 5.35 (br, 1H), 2.98 (dd, J=5.4 Hz, 1.8 Hz,2H), 1.55 (s, 3H), 1.16 (s, 3H), 1.17 (s, 3H)

MS (m/z): MH+ (339)

5-Isopropyl-3-methyl-4,5-dihydro-3H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide

(Hexane:Ethyl Acetate, 2:1, Rf=0.8, 560 Mg, 55%)

¹H NMR (CDCl₃) δ 9.18 (s, 1H), 8.20 (s, 1H), 8.05 (dd, J=1.0 Hz, 0.2 Hz,1H), 7.85 (d, J=0.9 Hz, 1H), 4.36 (dd, J=1.2 Hz, 0.6 Hz, 1H), 2.16 (q,J=0.7 Hz, 1H), 1.80 (m, 2H), 1.55 (s, 3H), 1.22 (d, J=0.7 Hz, 3H), 1.00(d, J=0.7 Hz, 3H)

MS (m/z): M+ (338)

EXAMPLE 455-(4-Methoxy-phenyl)-3-methyl-4,5-dihydro-3H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide Compound #10

Following the procedure described in Example 29,4-methyl-2-[(1E)-(4-methoxyphenyl)methylidene]benzenesulfonyl hydrazonewas reacted to yield the title compound as a white solid.

¹H NMR (CDCl₃) δ 9.85 (s, 1H), 8.16 (s, 1H), 7.95 (d, J=0.6 Hz, 1H),7.76 (d, J=0.6 Hz, 1H), 7.58 (d, J=0.6 Hz, 2H), 6.90 (d, J=0.6 Hz, 2H),5.68 (br, 1H), 3.82 (s, 3H), 3.30 (dd, J=3.9 Hz, 1.3 Hz, 1H), 1.65 (s,3H)

MS (m/z): M+ (403)

EXAMPLE 463-Methyl-5-pentafluorophenyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide Compound #9

Following the procedure described in Example 29,4-methyl-2-[(1E)-(pentafluorophenyl)methylidene]benzenesulfonylhydrazone was reacted to yield the title compound as a white solid.

¹H NMR (CDCl₃) δ 9.53 (s, 1H), 8.16 (s, 1H), 8.00 (d, J=0.6 Hz, 1H),7.79 (d, J=0.6 Hz, 1H), 6.27 (s, 1H), 3.40 (dd, J=6.0 Hz, 1.8 Hz, 1H),1.67 (s, 3H)

MS (m/z): M+ (463)

EXAMPLE 47 3,5-Dimethyl-4,5-dihydro-3H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide and3,5-Dimethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide Compound #97 and Compound #60

Diazoethane (˜0.5 M, 20 mL) in diethyl ether (which may be prepared byaccording to known methods) was added into2-methyl-N-(4-cyano-3-trifluoromethyl-phenyl)-acrylamide (250 mg, 1mmoL) in THF (2 mL) at room temperature. The solution was stirred atroom temperature for 72 hours. The solvent was removed and the residuewas purified by column chromatography to yield the title compounds as awhite solids.

3,5-Dimethyl-4,5-dihydro-3H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide

¹H NMR (CDCl₃) δ 9.06 (s, 1H), 8.16 (s, 1H), 7.99 (d, J=0.6 Hz, 1H),7.82 (d, J=0.6 Hz, 1H), 4.58 (m, 1H), 2.06 (dd, J=1.3 Hz, 0.5 Hz, 1H),1.59 (m, 1H), 1.56 (s, 3H)

MS (m/z): MNa+ (333)

3,5-Dimethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide

¹H NMR (CDCl₃) δ 9.85 (s, br, 1H0, 8.05 (s, 1H), 7.95 (d, J=7.5 Hz, 1H),7.75 (d, J=7.5 Hz, 1H), 2.95 (abq, J=12.5 Hz, 2H), 1.98 (s, 3H), 1.55(s, 3H)

MS (m/z): MH+ (311), MH− (309).

EXAMPLE 48 5-Ethyl-3-methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide and5-Ethyl-3-methyl-4,5-dihydro-3H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide Compound #15 and Compound #58

Following the procedure described in Example 29, the mixture of4-methyl-2-[(1E)-propylidene]benzenesulfonyl hydrazone was reacted toyield the two title compounds as a white solids.

5-Ethyl-3-methyl-4,5-dihydro-3H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide

(Hexane:Ethyl Acetate, 2:1, Rf=0.30)

¹H NMR (CDCl₃) δ 9.09 (s, 1H), 8.18 (s, 1H), 8.00 (d, J=0.6 Hz, 1H),7.98 (d, J=0.6 Hz, 1H), 4.48 (m, 1H), 2.10 (m, 2H), 2.00 (m, 1H), 1.65(m, 1H), 1.56 (s, 3H), 1.01 (t, J=0.7 Hz, 3H)

MS (m/z): MNa+ (347)

5-Ethyl-3-methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide

(Hexane:Ethyl Acetate, 2:1, Rf=0.10)

¹H NMR (CDCl₃) δ 9.89 (s, 1H), 8.14 (s, 1H), 7.95 (d, J=0.6 Hz, 1H),7.80 (d, J=0.6 Hz, 1H), 5.33 (m, 1H), 2.95 (dd, J=6.0 Hz, 1.4 Hz, 2H),2.35 (q, J=0.6 Hz, 2H), 1.58 (s, 3H), 1.18 (t, J=0.6 Hz, 3H)

MS (m/z): MNa+ (347)

EXAMPLE 49 5-Isobutyl-3-methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide and5-Isobutyl-3-methyl-4,5-dihydro-3H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide Compound #11 and Compound #61

Following the procedure described in Example 29,4-methyl-2-[(1E)-3-methylbutylidene]benzenesulfonyl hydrazone wasreacted to yield the two title compounds as a white solids.

5-Isobutyl-3-methyl-4,5-dihydro-3H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide

(Hexane:Ethyl Acetate, 2:1, Rf=0.80)

¹H NMR (CDCl₃) δ 9.10 (s, 1H), 8.17 (s, 1H), 8.00 (d, J=0.6 Hz, 1H),7.82 (d, J=0.6 Hz, 1H), 4.55 (q, J=0.5 Hz, 1H), 2.00 (m, 3H), 1.60 (m,1H), 1.57 (s, 3H), 1.39 (m, 1H), 1.04 (t, J=0.5 Hz, 3H)

MS (m/z): MNa+ (375)

5-Isobutyl-3-methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide

(Hexane:Ethyl Acetate, 2:1, Rf=0.20)

¹H NMR (CDCl₃) δ 9.86 (s, 1H), 8.12 (s, 1H), 7.93 (d, J=0.6 Hz, 1H),7.77 (d, J=0.6 Hz, 1H), 5.39 (br, 1H), 2.90 (dd, J=5.4 Hz, 1.3 Hz, 2H),2.19 (d, J=0.5 Hz, 2H), 1.91 (m, 1H), 1.57 (s, 3H), 0.93 (m, 6H)

MS (m/z): M+ (353)

EXAMPLE 503-Methyl-5-(2-methylsulfanyl-ethyl)-4,5-dihydro-3H-pyrazole-3-carboxylicacid (4-cyano-3-trifluoromethyl-phenyl)-amide Compound #59

Following the procedure described in Example 29,4-methyl-2-[(1E)-3-(methylthio)propylidene]benzenesulfonyl hydrazone wasreacted to yield the title compound as a white solid.

¹H NMR (CDCl₃) δ 9.02 (s, 1H), 8.15 (s, 1H), 7.98 (d, J=0.6 Hz, 1H),7.82 (d, J=0.6 Hz, 1H), 4.71 (q, J=0.5 Hz, 1H), 2.82 (m, 2H), 2.35 (m,1H), 2.11 (s, 3H), 2.08 (m, 1H), 1.95 (m, 1H), 1.60 (m, 1H), 1.57 (s,3H)

MS (m/z): MNa+ (393).

EXAMPLE 51 3-Methyl-5-propyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide and3-Methyl-5-propyl-4,5-dihydro-3H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide Compound #14 and Compound #62

Following the procedure described in Example 29,4-methyl-2-[(1E)-butylidene]benzenesulfonyl hydrazone was reacted toyield the two title compounds as a white solids.

3-Methyl-5-propyl-4,5-dihydro-3H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide

(Hexane:Ethyl Acetate, 2:1, Rf=0.70)

¹H NMR (CDCl₃) δ 9.11 (s, 1H), 8.11 (s, 1H), 7.93 (d, J=0.6 Hz, 1H),7.70 (d, J=0.6 Hz, 1H), 4.42 (q, J=0.5 Hz, 1H), 2.00 (m, 3H), 1.60 (m,3H), 1.49 (s, 3H), 1.00 (t, J=0.5 Hz, 3H)

MS (m/z): M+ (338)

3-Methyl-5-propyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide

(Hexane:Ethyl Acetate, 2:1, Rf=0.15)

¹H NMR (CDCl₃) δ 9.88 (s, 1H), 8.13 (s, 1H), 7.95 (d, J=0.6 Hz, 1H),7.79 (d, J=0.6 Hz, 1H), 5.39 (s, 1H), 2.90 (dd, J=5.8, 1.2 Hz, 2H), 2.29(t, J=0.6 Hz, 2H), 1.57 (m, 2H), 1.56 (s, 3H), 0.95 (t, J=0.5 Hz, 3H)

MS (m/z): M+ (338).

EXAMPLE 525-(4-Acetylamino-phenyl)-3-methyl-3,4-dihydro-2H-pyrazole-3-carboxylicacid (4-cyano-3-trifluoromethyl-phenyl)-amide Compound #33

Following the procedure described in Example 29,4-methyl-2-[(1E)-4-(acetamidophenyl)methylidene]benzenesulfonylhydrazone was reacted with2-methyl-N-(4-cyano-3-trifluoromethyl-phenyl)-acrylamide to yield thetitle compound as a white solid.

¹H NMR (CDCl₃) δ 9.70 (s, 1H), 8.11 (s, 1H), 7.93-7.79 (m, 2H), 7.55 (s,4H), 5.65 (s, 1H), 3.82 (dd, J=4.8, 2.4 Hz, 2H), 2.20 (s, 3H), 2.00 (s,3H).

MS (m/z): M+ (430)

EXAMPLE 535-(4-Acetylamino-phenyl)-3-methyl-3,4-dihydro-2H-pyrazole-3-carboxylicacid (4-nitro-3-trifluoromethyl-phenyl)-amide Compound #34

Following the procedure described in Example 29,4-methyl-2-[(1E)-4-(acetamidophenyl)methylidene]benzenesulfonylhydrazone was reacted with2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-acrylamide to yield thetitle compound as a yellow solid.

¹H NMR (CDCl₃) δ 8.30 (s, 1H), 8.15-8.01 (m, 2H), 7.58 (m, 4H), 3.82(dd, J=7.5, 2.4 Hz, 2H), 2.05 (s, 3H), 2.00 (s, 3H).

MS (m/z): M+ (450), M− (448)

EXAMPLE 543-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-phenyl)-amide Compound #20

Following the procedure described in Example 29,4-methyl-2-[(1E)-2,2,2-trifluoroethylidene]benzenesulfonyl hydrazone wasreacted with 2-methyl-N-(4-cyano-phenyl)-acrylamide to yield the titlecompound as a yellow solid.

¹H NMR (CDCl₃) δ 9.05 (s, 1H), 7.70-7.60 (m, 4H), 5.95 (s, 1H), 3.15(dd, J=6.0, 2.4 Hz, 2H), 1.60 (s, 3H).

MS (m/z): M− (295)

EXAMPLE 553-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-chloro-3-trifluoromethyl-phenyl)-amide Compound #23

Following the procedure described Example 29,4-methyl-2-[(1E)-2,2,2-trifluoroethylidene]benzenesulfonyl hydrazone wasreacted with 2-methyl-N-(4-cyano-3-chloro-phenyl)-acrylamide to yieldthe title compound as a yellow solid.

¹H NMR (CDCl₃) δ 8.95 (s, 1H), 7.95 (s, 1H), 7.75 (m, 1H), 7.50 (m, 1H),6.00 (s, 1H), 3.15 (dd, J=6.0, 2.4 Hz, 2H), 1.60 (s, 3H).

MS (m/z): MH+ (374)

EXAMPLE 563-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(3,4-dichloro-phenyl)-amide Compound #24

Following the procedure described in Example 29,4-methyl-2-[(1E)-2,2,2-trifluoroethylidene]benzenesulfonyl hydrazone wasreacted with 2-methyl-N-(3,4-dichlorophenyl)-acrylamide to yield thetitle compound as a yellow solid.

¹H NMR (CDCl₃) δ 8.85 (s, 1H), 7.85 (s, 1H), 7.40 (m, 2H), 5.85 (s, 1H),3.15 (dd, J=6.0, 2.4 Hz, 2H), 1.60 (s, 3H).

MS (m/z): MH+ (341).

EXAMPLE 573-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-benzyl-phenyl)-amide Compound #18

Following the procedure described in Example 29,4-methyl-2-[(1E)-2,2,2-trifluoroethylidene]benzenesulfonyl hydrazone wasreacted with N-(4-Benzyl-phenyl)-2-methyl-acrylamide to yield the titlecompound as a yellow solid.

¹H NMR (CDCl₃) δ 8.60 (s, 1H), 8.00 (m, 1H), 7.30-7.10 (m, 8H), 5.40 (s,1H), 4.00 (s, 2H), 2.70 (s, 2H), 1.38 (s, 3H).

MS (m/z): MH+ (362)

EXAMPLE 583-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-benzoyl-phenyl)-amide Compound #17

Following the procedure described in Example 29,4-methyl-2-[(1E)-2,2,2-trifluoroethylidene]benzenesulfonyl hydrazone wasreacted with N-(4-benzoyl-phenyl)-2-methyl-acrylamide to yield the titlecompound as a yellow solid.

¹H NMR (CDCl₃) δ 9.00 (s, 1H), 7.85 (m, 2H), 7.75 (m, 2H), 7.58 (m, 5H),5.90 (s, 1H), 3.15 (dd, J=6.5, 2.1 Hz, 2H), 1.60 (s, 3H).

MS (m/z): MH+ (376)

EXAMPLE 593-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-phenoxy-phenyl)-amide Compound #19

Following the procedure described in Example 29, the title compound wasprepared as a white solid.

¹H NMR (CDCl₃) δ 8.75 (s, 1H), 7.55 (m, 2H), 7.30 (m, 2H), 7.10 (m, 5H),5.75 (s, 1H), 3.15 (dd, J=6.4, 2.1 Hz, 2H), 1.55 (s, 3H).

MS (m/z): MH+ (364).

EXAMPLE 603-Ethyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide Compound #30

Following the procedure described Example 29, the title compound wasobtained as a white solid.

¹H NMR (CDCl₃) δ 9.37 (s, 1H), 8.11 (s, 1H), 7.95-7.80 (m, 2H), 6.10 (s,1H), 3.22 (dd, J=6.0, 2.7 Hz, 2H), 2.05 (m, 2H), 1.00 (t, J=1.5 Hz, 3H).

MS (m/z): MH+ (379).

EXAMPLE 613-Propyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide Compound #73

Following the procedure described in Example 29, the title compound wasobtained as a white solid.

¹H NMR (CDCl₃) δ 9.30 (s, 1H), 8.15 (s, 1H), 7.95 (m, 1H), 7.80 (m, 1H),6.25 (s, 1H), 3.15 (dd, J=6.0, 2.7 Hz, 2H), 2.00 (m, 2H), 1.30 (m, 2H),1.65 (t, J=1.0 Hz, 3H)

MS (m/z): MH+ (393).

EXAMPLE 623-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid4-methanesulfonyl-benzylamide Compound #27

Following the procedure described in Example 29, the title compound wasobtained as a white solid.

¹H NMR (CDCl₃) δ 7.90 (m, 2H), 7.45 (m, 2H), 6.75 (s, 1H), 4.50 (m, 2H),3.05 (s, 3H), 3.00 (dd, J=6.0, 2.7 Hz, 2H), 1.55 (s, 3H).

MS (m/z): MH+ (364).

EXAMPLE 633-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-phenylsulfanyl-phenyl)-amide Compound #28

Following the procedure described in Example 29, the title compound wasobtained as a white solid.

¹H NMR (CDCl₃) δ 8.75 (s, 1H), 7.55 (m, 2H), 7.35 (m, 2H), 7.23 (m, 5H),5.70 (s, 1H), 3.00 (dd, J=8.4, 2.4 Hz, 2H), 1.60 (s, 3H).

MS (m/z): MH+ (380)

EXAMPLE 643-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-benzenesulfonyl-phenyl)-amide Compound #32

3-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-phenylsulfanyl-phenyl)-amide (100 mg, 0.264 mmoL) in EtOAc (2 mL) atroom temperature was treated with Oxone (1.0 g) in water (10 mL). Sat.NaHCO₃ was added to adjust pH 7˜8. The reaction mixture was stirred for2 hrs. The mixture was then partitioned between ethyl acetate and water.The organic layers were combined and dried over Na₂SO₄, concentrated andpurified by silica gel column using ethyl acetate as eluent to affordthe title product.

¹H NMR (CDCl₃) δ 8.50 (s, 1H), 7.55 (m, 4H), 7.45 (m, 5H), 2.90 (dd,J=6.4, 2.1 Hz, 2H), 1.80 (s, 3H).

MS (m/z): MNa+ (432).

EXAMPLE 653-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid4-chloro-benzylamide Compound #29

Following the procedure described in Example 29, the title compound wasobtained as a white solid.

¹H NMR (CDCl₃) δ 7.35 (m, 4H), 5.70 (s, 1H), 4.50 (m, 2H), 3.00 (dd,J=6.0, 2.1 Hz, 2H), 1.50 (s, 3H).

MS (m/z): MH+ (319).

EXAMPLE 665-(3,4-Difluoro-phenyl)-3-methyl-3,4-dihydro-2H-pyrazole-3-carboxylicacid (4-cyano-3-trifluoromethyl-phenyl)-amide and5-(3,4-Difluoro-phenyl)-3-methyl-4,5-dihydro-3H-pyrazole-3-carboxylicacid (4-cyano-3-trifluoromethyl-phenyl)-amide Compound #2 and compound#53

Following the procedure described in Example 29, the title compoundswere obtained as white solids.

5-(3,4-Difluoro-phenyl)-3-methyl-3,4-dihydro-2H-pyrazole-3-carboxylicacid (4-cyano-3-trifluoromethyl-phenyl)-amide

MS (m/z): M+1 (409).

5-(3,4-Difluoro-phenyl)-3-methyl-4,5-dihydro-3H-pyrazole-3-carboxylicacid (4-cyano-3-trifluoromethyl-phenyl)-amide

MS (m/z): M+1 (409)

EXAMPLE 673-Methyl-5-(2,2,2-trifluoro-ethyl)-3,4-dihydro-2H-pyrazole-3-carboxylicacid (4-cyano-3-trifluoromethyl-phenyl)-amide Compound #75

Following the procedure described in Example 29, the title compound wasobtained as a white solid.

¹H NMR (CDCl₃) δ 9.60 (s, 1H), 8.15 (s, 1H), 7.95 (m, 1H), 7.80 (m, 1H),5.65 (s, 1H), 3.20 (m, 2H), 3.05 (dd, J=6.0, 2.4 Hz, 2H), 1.55 (s, 3H).

MS (m/z): MH+ (379).

EXAMPLE 68 5-Cyclopentyl-3-methyl-3,4-dihydro-2H-pyrazole-3-carboxylicacid (4-cyano-3-trifluoromethyl-phenyl)-amide Compound #48

Following the procedure described in Example 29, the title compound wasobtained as a white solid.

¹H NMR (CDCl₃) δ 9.85 (s, 1H), 8.10 (s, 1H), 7.95 (m, 1H), 7.80 (m, 1H),5.20 (s, 1H), 2.80 (dd, J=7.8, 2.4 Hz, 2H), 1.60 (m, 1H), 1.55 (s, 3H).MS (m/z): MH+ (365).

EXAMPLE 695-(2-Fluoro-3-hydroxy-phenyl)-3-methyl-3,4-dihydro-2H-pyrazole-3-carboxylicacid (4-cyano-3-trifluoromethyl-phenyl)-amide Compound #12

Following the procedure described in Example 29, the title compound wasobtained as a white solid.

¹H NMR (CDCl₃) δ 8.00 (s, 1H), 7.95 (m, 2H), 7.82 (s, 1H), 7.60 (m, 2H),7.35 (m, 2H), 7.15 (m, 2H), 3.60 (dd, J=25.0 Hz, 12.0 Hz, 2H), 1.35 (s,3H)

MS (m/z): M+1 (400).

EXAMPLE 70 3-Methyl-5-pyridin-3-yl-3,4-dihydro-2H-pyrazole-3-carboxylicacid (4-cyano-3-trifluoromethyl-phenyl)-amide Compound #77

Following the procedure described in Example 29, the title compound wasobtained as a white solid.

¹H NMR (CDCl₃) δ 9.70 (s, 1H), 8.80 (s, 1H), 8.60 (m, 1H), 8.10 (s, 1H),8.00 (m, 2H), 7.80 (m, 1H), 7.35 (m, 1H), 6.00 (s, 1H), 3.35 (dd, J=5.7,2.4 Hz, 2H), 1.65 (s, 3H). MS (m/z): MH+ (374).

EXAMPLE 715-(4-Fluoro-phenyl)-3-methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-chloro-3-trifluoromethyl-phenyl)-amide Compound #13

Following the procedure described in Example 29, the title compound wasobtained as a white solid.

¹H NMR (CDCl₃) δ7.80 (s, 1H), 7.45 (d, J=9.0 Hz, 1H), 6.80 (d, J=9.0 Hz,1H), 3.60 (dd, J=30.0 Hz, 18.0 Hz, 2H), 1.50 (s, 3H), 1.20 (s, 3H).

MS (m/z): M+1 (288).

EXAMPLE 725-(4-Acetylamino-phenyl)-3-methyl-3,4-dihydro-2H-pyrazole-3-carboxylicacid (4-chloro-3-trifluoromethyl-phenyl)-amide Compound #44

Following the procedure described in Example 29, the title compound wasobtained as a white solid.

¹H NMR (CDCl₃) δ 9.50 (s, 1H), 8.00 (s, 1H), 7.90 (s, 1H), 7.75 (m, 1H),7.50 (s, 4H), 7.45 (m, 1H), 5.70 (s, 1H), 3.25 (dd, J=5.4, 2.7 Hz, 2H),2.15 (s, 3H), 1.60 (s, 3H). MS (m/z): MH+ (439).

EXAMPLE 733-Methyl-5-[4-(2,2,2-trifluoro-acetylamino)-phenyl]-3,4-dihydro-2H-pyrazole-3-carboxylicacid (4-chloro-3-trifluoromethyl-phenyl)-amide Compound #46

Following the procedure described in Example 29, the title compound wasobtained as a white solid.

¹H NMR (CDCl₃) δ 9.50 (s, 1H), 8.80 (s, 1H), 8.00 (s, 1H), 7.75 (m, 1H),7.65 (s, 4H), 7.45 (m, 1H), 5.80 (s, 1H), 3.20 (dd, J=5.4, 2.4 Hz, 2H),1.60 (s, 3H). MS (m/z): MH+ (492).

EXAMPLE 745-(4-Acetylamino-benzyl)-3-methyl-3,4-dihydro-2H-pyrazole-3-carboxylicacid (4-cyano-3-trifluoromethyl-phenyl)-amide Compound #43

Following the procedure described in Example 29, the title compound wasobtained as a white solid.

¹H NMR (CDCl₃) δ 9.80 (s, 1H), 8.10 (s, 1H), 8.00 (s, 1H), 7.95 (m, 1H),7.75 (s, 1H), 7.55 (s, 4H), 5.75 (s, 1H), 3.30 (dd, J=5.4, 2.4 Hz, 2H),2.20 (s, 2H), 1.60 (s, 3H). MS (m/z): MNa+ (468).

EXAMPLE 75 Acetic acid4-[5-(4-cyano-3-trifluoromethyl-phenylcarbamoyl)-5-methyl-4,5-dihydro-1H-pyrazol-3-yl]-phenylester Compound #45

Following the procedure described in Example 29, the title compound wasobtained as a white solid.

¹H NMR (CDCl₃) δ 9.80 (s, 1H), 8.10 (s, 1H), 7.95 (m, 1H), 7.80 (m, 1H),7.55 (d, J=1.0 Hz, 2H), 6.85 (d, J=1.0 Hz, 2H), 5.60 (s, 1H), 3.30 (dd,J=5.4, 2.4 Hz, 2H), 2.0 (s, 3H), 1.60 (s, 3H). MS (m/z): MH+ (431).

EXAMPLE 765-(3-Acetylamino-phenyl)-3-methyl-3,4-dihydro-2H-pyrazole-3-carboxylicacid (4-cyano-3-trifluoromethyl-phenyl)-amide Compound #41

Following the procedure described in Example 29, the title compound wasobtained as a white solid.

¹H NMR (CDCl₃) δ 9.75 (s, 1H), 8.15 (s, 1H), 8.00-7.75 (m, 4H), 7.40 (m,1H), 7.25 (s, 1H), 5.80 (s, 1H), 3.25 (dd, J=5.4, 2.4 Hz, 2H), 2.20 (s,3H), 1.60 (s, 3H). MS (m/z): MH+ (431).

EXAMPLE 773-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-nitro-3-trifluoromethyl-phenyl)-amide Compound #74

Following the procedure described in Example 29, the title compound wasobtained as a white solid.

¹H NMR (CDCl₃) δ 9.30 (s, 1H), 8.10 (s, 1H), 8.00 (m, 2H), 6.10 (s, 1H),3.15 (dd, J=6.0, 2.4 Hz, 2H), 1.66 (s, 3H). MS (m/z): MH+ (385).

EXAMPLE 78 5-tert-Butyl-3-methyl-3,4-dihydro-2H-pyrazole-3-carboxylicacid (4-cyano-3-trifluoromethyl-phenyl)-amide Compound #86

Following the procedure described in Example 29, the title compound wasobtained as a white solid.

¹H NMR (CDCl₃) δ 9.78 (br, s, 1H), 8.12 (s, 1H), 7.92 (d, J=7.5 Hz, 1H),7.78 (d, J=7.5 Hz, 1H), 5.25 (br, s, 1H), 2.95 (abq, J=12.5 Hz, 2H),1.58 (s, 3H), 1.15 (s, 9H).

MS (m/z): MH+ (353), MH− (351).

EXAMPLE 79 5-tert-Butyl-3-methyl-3,4-dihydro-2H-pyrazole-3-carboxylicacid (4-nitro-3-trifluoromethyl-phenyl)-amide Compound #89

Following the procedure described in Example 29, the title compound wasobtained as a white solid.

¹H NMR (CDCl₃) δ 8.01 (d, J=7.0 Hz, 1H), 7.62 (s, 1H), 7.05 (d, J=7.0Hz, 1H), 6.10 (s, 1H), 5.48 (s, 1H), 3.25 (abq, J=12.5 Hz, 2H), 1.52 (s,3H), 1.25 (s, 9H).

MS (m/z): MH+ (373), MH− (371).

EXAMPLE 805-(4-Cyano-3-trifluoromethyl-phenylcarbamoyl)-5-methyl-4,5-dihydro-1H-pyrazole-3-carboxylicacid ethyl ester Compound #84

Following the procedure described in Example 31, the title compound wasobtained as a white solid.

¹H NMR (CDCl₃) δ 99.18 (s, br, 1H), 8.11 (s, 1H), 7.98 (d, J=7.2 Hz,1H), 7.81 (d, J=7.2 Hz, 1H), 6.25 (s, 1H), 4.32 (q, J=8.5 Hz, 2H), 3.25(abq, J=12.5 Hz, 2H), 1.62 (s, 3H), 1.45 (t, J=8.5 Hz, 3H).

MS (m/z): MH+ (369), MH− (367).

EXAMPLE 815-(4-Nitro-3-trifluoromethyl-phenylcarbamoyl)-5-methyl-4,5-dihydro-1H-pyrazole-3-carboxylicacid ethyl ester Compound #83

Following the procedure described in Example 31, the title compound wasobtained as a white solid.

¹H NMR (CDCl₃) δ 9.22 (s, br, 1H), 8.11 (s, 1H), 8.02 (d, J=6.5 Hz, 1H),8.00 (d, J=6.5 Hz, 1H), 6.38 (s, 1H), 4.32 (q, J=8.5 Hz, 2H), 3.25 (abq,J=12.5 Hz, 2H), 1.61 (s, 3H), 1.48 (t, J=8.5 Hz, 3H).

MS (m/z): MH+ (389), MNa+ (411).

EXAMPLE 825-(4-Bromo-3-trifluoromethyl-phenylcarbamoyl)-5-methyl-4,5-dihydro-1H-pyrazole-3-carboxylicacid ethyl ester Compound #85

Following the procedure described in Example 31, the title compound wasobtained as a white solid.

¹H NMR (CDCl₃) δ 8.95 (s, br, 1H), 7.98 (s, 1H), 7.65 (m, 2H), 6.35 (s,br, 1H), 4.33 (q, J=7.8 Hz, 2H), 3.15 (abq, J=10.5 z, 2H), 1.58 (s, 3H),1.48 (t, J=7.8 Hz, 2H).

MS (m/z): MH+ (423)

EXAMPLE 833-Methyl-5-[4-(2,2,2-trifluoro-acetylamino)-phenyl]-3,4-dihydro-2H-pyrazole-3-carboxylicacid (4-nitro-3-trifluoromethyl-phenyl)-amide Compound #37

Following the procedure described in Example 29, the title compound wasobtained as a white solid.

¹H NMR (C₆D₆) δ8.95 (s, 1H), 7.62 (s, 1H), 7.50 (d, J=7.8 Hz, 2H), 7.35(d, J=7.0 Hz, 1H), 7.20 (d, J=7.5 Hz, 2H), 7.18 (d, J=7.0 Hz, 1H), 4.95(s, 1H), 2.80 (abq, J=15.6 Hz, 2H), 1.62 (s, 3H).

MS (m/z): MH+ (504), MH− (502)

EXAMPLE 845-(4-Acetylamino-phenyl)-3-methyl-3,4-dihydro-2H-pyrazole-3-carboxylicacid (3,4-dicyano-phenyl)-amide Compound #38

Following the procedure described in Example 29, the title compound wasobtained as a white solid.

¹H NMR (CDCl₃) δ 9.79 (s, br, 1H), 8.25 (s, 1H), 7.88 (d, J=6.8 Hz, 1H),7.72 (d, J=6.8 Hz, 1H), 7.55 (s, 4H), 5.68 (s, 1H), 3.35 (abq, J=12.5 z,2H), 2.28 (s, 3H), 1.68 (s, 3H).

MS (m/z): MH+ (387).

EXAMPLE 85 3-Methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(3,4-dichloro-phenyl)-amide Compound #48

Following the procedure described in Example 31, the title compound wasobtained as a white solid.

¹H NMR (CDCl₃) δ 9.20 (s, 1H), 7.88 (s, 1H), 7.45 (s, 2H), 6.82 (s, 1H),3.05 (abq, J=12.5 Hz, 2H), 1.58 (s, 3H). MS (m/z): MH+ (273).

EXAMPLE 86 5-Ethylsulfanylmethyl-3-methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide Compound #87

Following the procedure described in Example 29, the title compound wasobtained as a white solid.

¹H NMR (CDCl₃) δ 9.15 (s, br, 1H), 7.95 (s, 1H), 7.75 (m, 2H), 7.55 (s,1H), 4.35 (abq, J=10.5 Hz, 2H), 3.85 (abq, J=12.5 Hz, 2H), 2.65 (m,J=8.5 Hz, 2H), 1.42 (s, 3H), 1.32 (t, J=8.5 Hz, 3H).

MS (CI) m/z MH+ (371).

EXAMPLE 875-(4-Cyano-3-trifluoromethyl-phenylcarbamoyl)-5-methyl-4,5-dihydro-1H-pyrazole-3-carboxylicacid tert-butyl ester Compound #90

Following the procedure described in Example 31, the title compound wasobtained as a white solid.

¹H NMR (CDCl₃) δ 9.32 (s, br, 1H), 8.12 (s, 1H), 7.95 (d, J=7.5 Hz, 1H),7.75 (d, J=7.5 Hz, 1H), 6.45 (s, 1H), 3.15 (abq, J=10.5 Hz, 2H), 1.61(s, 3H), 1.52 (s, 9H).

MS (m/z): MH+ (397).

EXAMPLE 885-(4-Cyano-3-trifluoromethyl-phenylcarbamoyl)-5-methyl-4,5-dihydro-1H-pyrazole-3-carboxylicacid Compound #91

5-(4-Cyano-3-trifluoromethyl-phenylcarbamoyl)-5-methyl-4,5-dihydro-1H-pyrazole-3-carboxylicacid tert-butyl ester (450 mg, 1.135 mmoL) in trifluoroacetic acid (2mL) and DCM (2 mL) was stirred for 6 hrs at room temperature. Thereaction mixture was washed with water and brine. The organic layer wasdried over anhydrous Na₂SO₄, filtered and concentrated to give the titleproduct as a colorless oil.

¹H NMR (CDCl₃) δ 12.5 (s, br, 1H), 9.11 (s, 1H), 8.09 (s, 1H), 7.98 (d,J=7.5 Hz, 1H), 7.81 (d, J=7.5 Hz, 1H), 3.25 (abq, J=12.5 Hz, 2H), 1.61(s, 3H).

MS (m/z): MH+ (341)

EXAMPLE 89 5-Hydroxymethyl-3-methyl-3,4-dihydro-2H-pyrazole-3-carboxylicacid (4-cyano-3-trifluoromethyl-phenyl)-amide Compound #92

5-(4-Cyano-3-trifluoromethyl-phenylcarbamoyl)-5-methyl-4,5-dihydro-1H-pyrazole-3-carboxylicacid (150 mg, 0.441 mmoL) in THF (2 mL) was treated dropwise withborane-THF complex (882 μL, 0.882 mmoL) at −78° C. over 10 min. Theresulting solution was stirred for another 10 min. and then quenchedwith MeOH. The solvent was removed and the residue was partitionedbetween water and DCM. The aqueous layer was extracted with DCM (3×).The combined organic layer was washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The crude product waspurified by silica gel using 2:1 hexanes:ethyl acetate as eluent toyield the title compound as a white solid.

¹H NMR (CDCl₃) δ 9.65 (s, 1H), 8.25 (s, 1H), 7.95 (d, J=7.8 Hz, 1H),7.75 (d, J=7.8 Hz, 1H), 5.50 (s, 1H), 4.25 (abq, J=10.5 Hz, 2H), 2.95(abq, J=12.5 Hz, 2H), 1.48 (s, 3H).

MS (m/z): MH+ (327).

EXAMPLE 903-Methyl-5-pentafluoroethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide Compound #98

Following the procedure described in Example 31, the title compound wasobtained as a white solid.

¹H NMR (MeOD) δ8.21 (s, 1H), 8.10 (d, J=6.5 Hz, 1H), 7.88 (d, J=6.5 Hz,1H), 3.30 (abq, J=12.5 Hz, 2H), 1.68 (s, 3H).

EXAMPLE 913-Methyl-5-pentafluoroethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-nitro-3-trifluoromethyl-phenyl)-amide Compound #99

Following the procedure described in Example 31, the title compound wasobtained as a white solid.

¹H NMR (CDCl₃) δ 9.21 (s, br, 1H), 8.12 (s, 1H), 8.02 (s, 2H), 6.05 (s,br, 1H), 3.18 (abq, J=13.5 Hz, 2H), 1.62 (s, 3H)

MS (m/z): MH− (413)

EXAMPLE 92 3-Methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-benzoyl-phenyl)-amide and3-Methyl-5-trimethylsilanyl-pyrazolidine-3-carboxylic acid(4-benzoyl-phenyl)-amide Compound #16 and Compound #63

Following the procedure described in Example 31, the title compoundswere obtained as white solids.

3-Methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-benzoyl-phenyl)-amide

¹H NMR (CDCl₃) δ 9.42 (s, br, 1H), 7.85 (d, J=8.5 Hz, 2H), 7.76 (d,J=7.8 Hz, 2H), 7.70 (d, J=8.5 Hz, 2H), 7.65 (t, J=7.8 Hz, 1H), 7.60 (t,J=8.5 Hz, 2H), 6.82 (s, 1H), 5.45 (s, 1H), 3.01 (abq, J=13.5 Hz, 2H),1.55 (s, 3H).

MS (m/z): MH+ (308), MNa+ (330).

3-methyl-5-trimethylsilanyl-pyrazolidine-3-carboxylic acid(4-benzoyl-phenyl)-amide

¹H NMR (CDCl₃) 6 (1:1 isomers) 8.45 (s, 1H, isomer 1), 8.25 (s, 1H,isomer 2), 7.30˜7.75 (m, 9H, both isomers), 4.40 (m, 1H, isomer 1), 4.32(m, 1H, isomer 2), 2.48 (m, 1H, isomer 1), 2.10 (m, 1H, isomer 2), 1.72(m, 1H, isomer 1), 1.32 (m, 1H, isomer 2), 1.55 (s, 3H, isomer 1), 1.50(s, 3H, isomer 2), 0.15 (s, 9H, isomer 1), 0.10 (s, 9H, isomer 2).

EXAMPLE 93 3-Methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-phenyl)-amide and3-methyl-5-trimethylsilanyl-4,5-dihydro-3H-pyrazole-3-carboxylic acid(4-cyano-phenyl)-amide Compound #21 and Compound #65

Following the procedure described in Example 31, the title compoundswere obtained as white solids.

3-Methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-phenyl)-amide

¹H NMR (CDCl₃) δ 9.45 (s, br, 1H), 7.75 (d, J=7.8 Hz, 2H), 7.62 (d,J=7.8 Hz, 2H), 6.85 (s, 1H), 5.45 (s, br, 1H), 3.01 (abq, J=12.5 Hz,2H), 1.55 (s, 3H).

MS (m/z): MH+ (229), MNa+ (251), MH− (227)

3-Methyl-5-trimethylsilanyl-4,5-dihydro-3H-pyrazole-3-carboxylic acid(4-cyano-phenyl)-amide

¹H NMR (CDCl₃) 6 (2:1 isomers) 9.35 (s, 1H, isomer 1), 8.51 (s, 1H,isomer 2), 7.51˜7.70 (m, 4H, both isomers), 4.45 (m, 1H, isomer 1), 4.40(m, 1H, isomer 2), 2.08 (m, 1H, both isomers), 1.72 (m, 1H, bothisomers), 1.58 (s, 3H, isomer 1), 1.45 (s, 3H, isomer 2), 0.15 (s, 9H,isomer 1), 0.05 (s, 9H, isomer 2).

EXAMPLE 94 3-Methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid3-phenoxy-benzylamide and3-Methyl-5-trimethylsilanyl-4,5-dihydro-3H-pyrazole-3-carboxylic acid3-phenoxy-benzylamide Compound #22 and Compound #66

Following the procedure described in Example 31, the title compoundswere obtained as white solids.

3-Methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid 3-phenoxy-benzylamide

¹H NMR (CDCl₃) δ 7.55 (s, br, 1H), 7.32 (m, 2H), 7.25 (m, 2H), 7.12 (t,J=7.8 Hz, 1H), 6.98 (m, 4H), 6.72 (s, 1H), 5.25 (s, br, 1H), 4.40 (d,J=5.2 Hz, 2H), 2.88 (abq, J=12.5 Hz, 2H), 1.48 (s, 3H).

MS (m/z): MH+ (310), MNa+ (332), MH− (308)

3-Methyl-5-trimethylsilanyl-4,5-dihydro-3H-pyrazole-3-carboxylic acid3-phenoxy-benzylamide

¹H NMR (CDCl₃) 6 (1:1 isomers) 6.85˜7.36 (m, 9H, both isomers), 6.75 (s,1H, isomer 1), 6.51 (s, 1H, isomer 2), 4.51 (m, 2H, both isomers), 4.40(m, 1H, isomer 1), 4.35 (m, 1H, isomer 2), 2.32 (m, 1H, isomer 1), 2.00(m, 1H, isomer 2), 1.65 (m, 1H, isomer 1), 1.58 (s, 3H, isomer 1), 1.50(s, 3H, isomer 2), 1.32 (m, 1H, isomer 2), 0.15 (s, 9H, isomer 1), 0.05(s, 9H, isomer 2).

EXAMPLE 95 3-Methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid3-methanesulfonyl-benzylamide and3-Methyl-5-trimethylsilanyl-4,5-dihydro-3H-pyrazole-3-carboxylic acid3-methanesulfonyl-benzylamide Compound #26 and Compound #67

Following the procedure described in Example 31, the title compoundswere obtained as white solids.

3-Methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid3-methanesulfonyl-benzylamide

¹H NMR (CDCl₃) δ7.90 (d, J=7.5 Hz, 2H), 7.72 (br, s, 1H), 7.42 (d, J=7.5Hz, 2H), 6.78 (s, 1H), 5.28 (s, 1H), 4.50 (d, J=4.8 Hz, 2H), 3.15 (s,3H), 2.98 (abq, J=12.5 Hz, 2H), 1.48 (s, 3H).

MS (m/z): MH+ (296), MNa+ (318), MH− (294)3-Methyl-5-trimethylsilanyl-4,5-dihydro-3H-pyrazole-3-carboxylic acid3-methanesulfonyl-benzylamide:

¹H NMR (CDCl₃) 6 (1:1 isomers) 7.82 (m, 2H, both isomers), 7.40 (m, 2H,both isomers), 7.15 (s, 1H, isomer 1), 6.90 (s, 1H, isomer 2), 4.51 (m,2H, both isomers), 4.40 (m, 1H, isomer 1), 4.32 (m, 1H, isomer 2), 2.32(m, 1H, isomer 1), 1.92 (m, 1H, isomer 2), 1.62 (m, 1H, isomer 1), 1.58(s, 3H, isomer 1), 1.50 (s, 3H, isomer 2), 1.28 (m, 1H, isomer 2), 0.15(s, 9H, isomer 1), 0.05 (s, 9H, isomer 2).

EXAMPLE 96(R)-3-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide and(S)-3-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide Compound #35 and Compound #36

A racemic mixture of3-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide (500 mg) was loaded onto aChiralPak AD chiral HPLC column (50 mm I.D.×500 mm L) and eluted with10% ethanol in heptane at the 70 mL/min flow rate. Two peaks werecollected separately and were removed under vacuum to yield:

-   (R)-3-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic    acid (4-cyano-3-trifluoromethyl-phenyl)-amide as peak two.

MS (CI) m/z 365(M+H⁺)

-   and    (S)-3-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic    acid (4-cyano-3-trifluoromethyl-phenyl)-amide as peak one.

MS (CI) m/z 365(M+H⁺)

EXAMPLE 97(R)-3-Ethyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide and(S)-3-Ethyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide Compound #81 and Compound #82

The racemic mixture of3-ethyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide (500 mg) was loaded onto aChiralPak AD chiral HPLC column (50 mm I.D.×500 mm L) and eluted with10% ethanol in heptane at the 70 mL/min flow rate. Two peaks werecollected separately and were removed under vacuum to yield:

-   (R)-3-ethyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic    acid (4-cyano-3-trifluoromethyl-phenyl)-amide as peak two.

MS (CI) m/z 379(M+H⁺)

-   and    (S)-3-ethyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic    acid (4-cyano-3-trifluoromethyl-phenyl)-amide as peak one.

MS (CI) m/z 379(M+H⁺)

EXAMPLE 98 3-Methyl-pyrazolidine-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide Compound #100

3-Methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide (1.5 g, 5.1 mmoL) in glacialacetic acid (5 mL) was treated with powder NaCNBH₃ (750 mg, 12.7 mmoL)at room temperature. The reaction mixture was stirred for 1 hr. Thereaction mixture was then neutralized with saturated NaHCO₃ andextracted with ethyl acetate (3×). The combined organic layer was washedwith water and brine, dried over Na₂SO₄, filtered and concentrated toyield the title compound as a colorless oil.

¹H NMR (CDCl₃) δ 9.89 (s, br, 1H), 8.11 (s, 1H), 8.02 (d, J=7.5 Hz, 1H),7.77 (d, J=7.5 Hz, 1H), 3.28 (t, J=8.5 Hz, 2H), 2.65 m, 2H), 1.61 (s,3H).

MS (CI) m/z MH+ (299), MH− (297).

EXAMPLE 99 3-Methyl-1-(2,2,2-trifluoro-acetyl)-pyrazolidine-3-carboxylicacid (4-cyano-3-trifluoromethyl-phenyl)-amide Compound #101

3-Methyl-pyrazolidine-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide (350 mg, 0.84 mmoL) in DCM (2mL) was treated with Et₃N (118 μL, 0.84 mmoL) and TFAA (117 μL, 0.84mmoL) at 0° C. The reaction mixture was stirred for 30 min and thenpartitioned between saturated NaHCO₃ and DCM. The organic layer waswashed with water and brine, dried over Na₂SO₄, filtered andconcentrated to yield the title compound as a colorless oil, which wasthen purified by silica gel column using hexanes:ethyl acetate 1:1 aseluent to yield the title compound as a white solid.

¹H NMR (CDCl₃) δ 9.22 (s, br, 1H), 8.08 (s, 1H), 7.82 (s, 2H), 3.72 (m,2H), 3.10 (m, 1H0, 2.05 (m, 1H), 1.65 (s, 3H).

MS (CI) m/z MNa+ (417), MH− (393).

EXAMPLE 100 1-(4-Acetylamino-benzyl)-3-methyl-pyrazolidine-3-carboxylicacid (4-cyano-3-trifluoromethyl-phenyl)-amide Compound #102

3-Methyl-pyrazolidine-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide (410 mg, 1.38 mmoL) and (225mg, 1.38 mmoL) in MeOH (5 mL) at room temperature was treated withNaCNBH₃ (216 mg, 3.44 mmoL). The reaction mixture was stirred at roomtemperature overnight. The solvent was removed and the residue waspartitioned between ethyl acetate and water. The aqueous layer wasextracted with ethyl acetate (3×). The combined organic layer was washedwith water and brine, dried over Na₂SO₄, filtered and concentrated toyield the title compound as a colorless oil, which was then purified bysilica gel column using hexanes:ethyl acetate 1:1 as eluent to yield thetitle compound as a white solid.

¹H NMR (CDCl₃) δ 8.05 (s, 1H), 7.85 (d, J=6.5 Hz, 1H), 7.62 (d, J=6.5Hz, 1H), 7.52 (d, J=7.0 Hz, 2H), 7.25 (d, J=7.0 Hz, 2H), 3.75 (abq,J=12.5 Hz, 2H), 3.18 (m, 1H), 2.65 (m, 3H), 2.15 (s, 3H), 1.48 (s, 3H).

MS (m/z): MNa+ (468)

EXAMPLE 101 2-Methyl-N-pyridin-4-yl-acrylamide

LiHMDS (1.0 N in THF, 23.6 mmoL, 24 mL) was added dropwise into pyridine(11.8 mmoL, 1.11 g) in THF (10 mL) at 0° C. After 10 min,2-methyl-acryloyl chloride (11.8 mmoL, 1.43 mL) was added into thereaction at 0° C. The reaction was then slowly warmed to roomtemperature. The solvent was removed and the residue was partitionedbetween Et₂O and water. The Et₂O layer was washed with brine, dried overanhydrous Na₂SO₄, filtered and concentrated to yield a brown oil. Thecrude material (the brown oil) was then purified by columnchromatography (silica gel, EtOAc as eluent) to yield the title compoundas a reddish oil.

¹H NMR (CDCl₃) δ 8.45 (br, s, 1H), 8.22 (d, J=7.5 Hz, 2H), 7.45 (d,J=7.5 Hz, 2H), 5.68 (s, 1H), 5.26 (s, 1H), 1.89 (s, 3H).

EXAMPLE 102 N-(6-Chloro-pyridin-3-yl)-2-methyl-acrylamide

Following the procedure described in Example 1, the title compound wasobtained as a grey solid.

¹H NMR (CDCl₃) δ 8.45 (s, 1H), 8.20 (d, J=7.5 Hz, 1H), 7.61 (s, br, 1H),7.34 (d, J=7.5 Hz, 1H), 5.88 (s, 1H), 5.55 (s, 1H), 2.05 (s, 3H).

EXAMPLE 103 N-(6-Cyano-pyridin-3-yl)-2-methyl-acrylamide

Following the procedure described in Example 1, the title compound wasobtained as a grey solid.

¹H NMR (CDCl₃) δ 8.65 (s, 1H), 8.48 (d, J=8.5 Hz, 1H), 7.88 (s, br, 1H),7.70 (d, J=8.5 Hz, 1H), 5.88 (s, 1H), 5.62 (s, 1H), 2.12 (s, 3H).

MS (m/z): MH+ (188).

EXAMPLE 1045-(4-Fluoro-phenyl)-3-methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acidpyridin-4-ylamide Compound #93

Following the procedure described in Example 29, the title compound wasobtained as a pale solid.

¹H NMR (CDCl₃) δ 9.45 (br, s, 1H), 8.35 (d, J=7.5 Hz, 2H), 7.38 (d,J=7.5 Hz, 2H), 7.15 (d, J=6.5 Hz, 2H), 7.04 (d, J=6.5 Hz, 2H), 3.36˜3.22(Abq, J=12.5 Hz, 2H), 1.62 (s, 3H).

MS (m/z): MH⁺ (299)

EXAMPLE 105 3-Methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(6-chloro-pyridin-3-yl)-amide Compound #80

Following the procedure described in Example 31, the title compound wasobtained as a white solid in pure form.

¹H NMR (CDCl₃) δ 9.05 (s, br, 1H), 8.25 (s, 1H), 7.95 (d, J=7.5 Hz, 1H),7.10 (d, J=7.5 Hz, 1H), 7.05 (s, 1H), 5.55 (s, br, 1H), 2.72 (abq,J=12.5 Hz, 2H), 1.25 (s, 3H).

MS (m/z): MH+ (239)

EXAMPLE 1063-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(6-chloro-pyridin-3-yl)-amide Compound #88

Following the procedure described in Example 29, the title compound wasobtained as a white solid.

¹H NMR (CDCl₃) δ 8.90 (s, 1H), 8.55 (m, 1H), 8.15 (m, 1H), 7.30 (m, 1H),6.10 (s, 1H), 3.15 (dd, J=6.0, 2.7 Hz, 2H), 1.60 (s, 3H).

MS (m/z): MH+ (307).

EXAMPLE 1073-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(6-cyano-pyridin-3-yl)-amide Compound #88

Following the procedure described in Example 29, the title compound wasobtained as a white solid.

¹H NMR (CDCl₃) δ 9.21 (s, br, 1H), 8.75 (s, 1H), 8.38 (d, J=7.5 Hz, 1H),7.70 (d, J=7.5 Hz, 1H), 6.05 (s, 1H), 3.20 (abq, J=11.5 Hz, 2H), 1.62(s, 3H).

MS (m/z): MNa+ (320).

EXAMPLE 1083-(4-Acetylamino-phenyl)-2,5-dimethyl-isoxazolidine-5-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide

2-Methyl-N-(4-cyano-3-trifluoromethyl-phenyl)-acrylamide (193 mg, 0.76mmoL) in xylene (5 mL) was treated withN-methyl-{4-(oxyimino-methyl)phenyl)acetamide (250 mg, 0.76 mmoL) (whichmay be prepared by known methods). The reaction mixture was then heatedto 50° C. and stirred for 6 hrs. The solvent was removed and the residuewas purified by silica gel column using 1:1 hexanes:ethyl acetate aseluent to yield the title compound as a white solid.

¹H NMR (CDCl₃) δ 9.42 (s, 1H), 8.12 (s, 1H), 7.98 (d, J=7.3 Hz, 1H),7.81 (d, J=7.3 Hz, 1H), 7.55 (s, 1H), 7.49 (d, J=8.0 Hz, 2H), 7.22 (d,J=8.0 Hz, 2H), 3.62 (t, J=6.4 Hz, 1H), 2.75 (m, 1H), 2.68 (s, 3H), 2.61(m, 1H), 2.18 (s, 3H), 1.62 (s, 3H).

MS (m/z): MH+ (447), MNa+ (469), MH− (445).

EXAMPLE 1093-(4-Acetylamino-phenyl)-2,5-dimethyl-isoxazolidine-5-carboxylic acid(4-nitro-3-trifluoromethyl-phenyl)-amide Compound #70

Following the procedure described in Example 108, the title compound wasobtained as a white solid.

¹H NMR (CDCl₃) δ 9.45 (s, br, 1H), 8.12 (s, 1H), 8.01 (m, 2H), 7.45 (d,J=7.8 Hz, 2H), 7.38 (s, 1H), 7.18 (d, J=7.8 Hz, 2H), 3.61 (t, J=6.5 Hz,1H), 2.81 (m, 1H), 2.68 (s, 3H), 2.61 (m, 1H), 2.18 (s, 3H), 1.62 (s,3H).

MS (m/z): MH+ (467), MNa+ (489)

EXAMPLE 110 2-Methyl-oxirane-2-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide

2-Methyl-N-(4-cyano-3-trifluoromethyl-phenyl)-acrylamide (1.35 g, 5.0mmol) in CH₂Cl₂ (15 ml) was treated by TFA (3.0 ml) at 0° C. To thereaction mixture was then added H₂O₂ (30%, 1.0 ml, 10.0 mmol) dropwise.The reaction mixture was stirred overnight and quenched by NaHCO₃, thenextracted by ethyl acetate. The organic layers were combined and driedover Na₂SO₄, concentrated and purified by silica gel column usinghexanes:ethyl acetate 4:1 as eluent to yield the title compound as awhite solid.

¹H NMR (CDCl₃) δ 8.40 (br. 1H), 8.10-7.80 (m, 3H), 5.85 (s, 1H), 5.60(s, 1H), 2.00 (s, 3H).

MS (m/z): MNa+ (293).

EXAMPLE 1113-Amino-N-(4-cyano-3-trifluoromethyl-phenyl)-2-hydroxy-2-methyl-propionamide

2-Methyl-oxirane-2-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide (1.0 g, 3.48 mmoL) wasdissolved in 7N NH₃/MeOH solution (10 mL) at room temperature. Thereaction mixture was stirred overnight and the solvent was removed toyield the title compound as pale yellow solid.

¹H NMR (CDCl₃) δ 9.58 (s, br, 1H), 8.15 (s, 1H), 7.95 (d, J=7.8 Hz, 1H),7.72 (d, J=7.8 Hz, 1H), 3.42 (d, J=9.8 Hz, 1H), 2.65 (d, J=9.8 Hz, 1H),1.48 (s, 3H)

MS (m/z): MH+ (288)

EXAMPLE 112 2,5-Dimethyl-4,5-dihydro-oxazole-5-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide Compound #103

BF₃.Etherate (1.0 mmol) was added to a mixture of2-methyl-oxirane-2carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide (135 mg, 0.5 mmol) inacetonitrile (2 mL) at 0° C. The reaction mixture was stirred at 0° C.for 1 h and then quenched with NaHCO₃, the organic layer was extractedwith ethyl acetate, washed with brine and concentrated to yield a crudeproduct. The crude product was purified on silica gel with ethyl acetateto yield the title compound as a solid.

¹H NMR (CDCl₃) δ 8.50 (s, 1H), 8.10 (s, 1H), 8.00 (d, J=9.0 Hz, 1H),7.80 (d, J=9.0 Hz), 1H), 4.00 (dd, J=105Ha, 15Ha, 2H), 2.10 (s, 3H),1.70 (s, 3H)

MS (m/z): MH+ (312), MNa+ (334).

EXAMPLE 113 2-(4-Acetylamino-phenyl)-5-methyl-oxazolidine-5-carboxylicacid (4-cyano-3-trifluoromethyl-phenyl)-amide Compound #72

2-Methyl-oxirane-2-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide (100 mg, 0.35 mmoL) and aceticacid 4-formyl-phenyl ester (57 mg, 0.35 mmoL) in MeOH (5 mL) was stirredat room temperature for 2 hr. Then, a catalytic amount of pTSA (˜10 mg)was added and the reaction mixture was stirred overnight. The solventwas removed and the residue was purified by silica gel column usinghexanes:ethyl acetate 2:1 as eluent to yield the title compound as awhite solid.

¹H NMR (CDCl₃) δ 9.60 (s, br, 1H), 8.31 (s, br, 1H), 8.08 (s, 1H), 7.92(d, J=6.8 Hz, 1H), 7.70 (d, J=7.5 Hz, 2H), 7.58 (d, J=7.5 Hz, 2H), 4.42(br, s, 1H), 4.02 (abq, J=12.5 Hz, 2H), 2.18 (s, 3H), 1.55 (s, 3H).

MS (m/z): MH+ (433)

EXAMPLE 114 2,5-Dimethyl-4,5-dihydro-oxazole-5-carboxylic acid(3,4-dichloro-phenyl)-amide Compound #104

Following the procedure described in Example 112, the title compound wasobtained as a white solid.

¹H NMR (CDCl₃) δ 7.80 (s, 1H), 7.45 (d, J=9.0 Hz, 1H), 6.80 (d, J=9.0Hz, 1H), 3.60 (dd, J=30.0 Hz, 18.0 Hz, 2H), 1.50 (s, 3H), 1.20 (s, 3H).

MS (m/z): MH+ (332), MNa+ (354)

EXAMPLE 115 2,5-Dimethyl-4,5-dihydro-oxazole-5-carboxylic acid(4-cyano-phenyl)-amide Compound #105

Following the procedure described in Example 112, the title compound wasobtained as a white solid.

¹H NMR (CDCl₃) δ 8.15 (s, 1H), 7.80 (dd, J=52.0 Hz, 9.0 Hz, 4H), 3.50(dd, J=60.0 Hz, 21.0 Hz, 2H), 1.90 (s, 3H), 1.40 (s, 3H)

MS (m/z): M+H₂O (262)

EXAMPLE 116 4-acetamido-N-(ethyl)-benzenecarbohydrazonoyl chloride

Following the procedure described in Example 21, starting fromN-[4-(ethyl-hydrazonomethyl)-phenyl]-acetamide, the title compound wasprepared as a white solid.

MS (m/z): MH+ (240).

EXAMPLE 1175-(4-Acetylamino-phenyl)-2-ethyl-3-methyl-3,4-dihydro-2H-pyrazole-3-carboxylicacid (4-cyano-3-trifluoromethyl-phenyl)-amide Compound #135

Following the procedure described in Example 23, starting from4-acetamido-N-(ethyl)-benzenecarbohydrazonoyl chloride, the titlecompound was prepared as an off-white solid.

MS (m/z): MH+ (458).

EXAMPLE 118 2-Ethyl-3,5-dimethyl-3,4-dihydro-2H-pyrazole-3-carboxylicacid (4-cyano-3-trifluoromethyl-phenyl)-amide Compound #146

3,5-Dimethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide (1 mmoL) was reacted with adiazoethane/diethyl ether solution (10 mmoL) in dioxane for about 5days. The reaction mixture was worked up by solvent evaporation andcolumn chromatography separation. The title compound was isolated as aminor product, as a white solid.

¹H NMR (CDCl₃) δ 9.68 (s, 1H), 8.07 (s, 1H), 7.85 (d, J=8.0 Hz, 1H),7.75 (d, J=8.0 Hz, 1H), 3.15 (m, 1H), 3.05 (abq, J=10.0 Hz, 1H), 2.80(m, 1H), 2.71 (abq, J=10.0 Hz, 1H), 1.98 (s, 3H), 1.40 (s, 3H), 1.35 (t,J=9.5 hz, 3H)

MS (m/z): MH⁺ 339.

EXAMPLE 119N-(4-Cyano-3-trifluoromethyl-phenyl)-2-trifluoromethyl-acrylamide

2-Trifluoromethyl-acrylic acid (36.0 mmoL) in thionyl chloride (2.86 mL)was refluxed for 30 min. Excess thionyl chloride was removed in vacuo toyield a residue. 4-Amino-2-trifluoromethyl-benzonitrile (36.0 mmoL) indiethyl ether (50 mL) was added dropwise to the residue at −40° C. Thereaction mixture was slowly warmed to room temperature. The reactionmixture was then partitioned between diethyl ether and water. Thediethyl ether layer was washed with saturated sodium bicarbonate, thenbrine, dried over anhydrous Na₂SO₄, filtered and concentrated to yield abrown oil. The crude material (the brown oil) was then purified bycolumn chromatography (silica gel, using ethyl acetate as eluent) toyield the title compound as yellow solid.

¹H NMR (CDCl₃) δ 8.25 (br, s, 1H), 7.60 (d, J=8.0 Hz, 1H), 6.95 (s, 1H),6.75 (d, J=8.0 Hz, 1H), 6.25 (s, 1H), 5.98 (s, 1H).

EXAMPLE 120 3,5-Bis-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylicacid (4-cyano-3-trifluoromethyl-phenyl)-amide Compound #112

Following the procedure described in Example 29, starting fromN-(4-cyano-3-trifluoromethyl-phenyl)-2-trifluoromethyl-acrylamide and4-methyl-2-[(1E)-2,2,2-trifluoroethylidene]benznenesulfonyl hydrazone,the title compound was prepared as a yellow solid.

¹H NMR (CDCl₃) δ9.18 (s, 1H), 8.11 (s, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.82(D, J=8.0 Hz, 1H), 7.05 (s, 1H), 3.62 (abq, J=9.0 Hz, 1H), 3.08 (abq,J=9.0 Hz, 1H)

MS (m/z): MH⁺ 419.

EXAMPLE 1215-(4-Cyano-3-trifluoromethyl-phenylcarbamoyl)-5-trifluoromethyl-4,5-dihydro-1H-pyrazole-3-carboxylicacid ethyl ester Compound #113

Following the procedure described in Example 31 starting fromN-(4-cyano-3-trifluoromethyl-phenyl)-2-trifluoromethyl-acrylamide andethyl diazoacetate, the title compound was prepared as a yellow solid.

¹H NMR (CDCl₃) δ 9.28 (s, 1H), 8.10 (s, 1H), 8.08 (d, J=8.0 Hz, 1H),7.82 (d, J=7.8 Hz, 1H), 7.70 (s, 1H), 4.32 (q, J=6.8 Hz, 2H), 3.72 (abq,J=8.5 Hz, 1H), 3.60 (abq, J=8.5 Hz, 1H), 1.35 (t, J=8.5 Hz, 3H)

MS (m/z): MH⁺ 423.

EXAMPLE 1225-Methyl-3-trifluoromethyl-4,5-dihydro-3H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide Compound #114

and 5-Methyl-3-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide Compound #116

Following the procedure described in Example 47, starting fromN-(4-cyano-3-trifluoromethyl-phenyl)-2-trifluoromethyl-acrylamide, thetitle compounds were prepared as off-white solids.

5-Methyl-3-trifluoromethyl-4,5-dihydro-3H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide

¹H NMR (CDCl₃) 6 diastereomer 1, 9.01 (s, 1H), 8.15 (s, 1H), 8.01 (d,J=7.5 Hz, 1H), 7.80 (d, J=7.5 Hz, 1H), 4.85 (m, 1H), 3.15 (m, 1H), 2.40(m, 1H), 1.55 (d, J=9.5 Hz, 3H); diastereomer 2, 8.55 (s, 1H), 8.05 (s,1H), 7.90 (d, J=8.0 Hz, 1H), 7.65 (d, J=8.0 Hz, 1H), 4.70 (m, 1H), 2.75(m, 1H), 1.80 (m, 1H), 1.65 (d, J=10.0 Hz, 3H).

5-Methyl-3-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide

¹H NMR (CDCl₃) δ 9.75 (br, s, 1H), 8.15 (s, 1H), 7.98 (d, J=6.5 Hz, 1H),7.80 (d, J=7.5 Hz, 1H), 6.25 (s, 1H), 3.45 (abq, J=8.5 Hz, 1H), 3.25(abq, J=8.5 Hz, 1H), 2.12 (s, 3H)

MS (m/z): MH⁺ 365.

EXAMPLE 123N-(4-Cyano-3-trifluoromethyl-phenyl)-2,2,2-trifluoro-N-(2-methyl-acryloyl)-acetamide

N-(4-Cyano-3-trifluoromethyl-phenyl)-2-methyl-acrylamide (4.4 mmoL) inDCM (15 mL) was reacted with pyridine (6 mL) followed by trifluoroaceticanhydride (4.4 mmoL) at 0° C. The reaction mixture was slowly warmed toroom temperature. The reaction mixture was partitioned between DCM andwater. The DCM layer was washed with saturated sodium bicarbonate, thenbrine, dried over anhydrous Na₂SO₄, filtered and concentrated to yield ayellow oil. The crude material (the yellow oil) was purified by columnchromatography (silica gel, using ethyl acetate as eluent) to yield thetitle compound as a yellow solid.

¹H NMR (CDCl₃) δ8.15 (s, 1H), 8.05 (d, J=8.5 Hz, 1H), 7.85 (d, J=8.5 Hz,1H), 6.25 (s, 1H), 5.81 (s, 1H), 5.65 (s, 1H), 2.05 (s, 3H). MS (m/z):MH⁺ 351.

EXAMPLE 1243-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-(2,2,2-trifluoro-acetyl)-amideCompound #115

Following the procedure described in Example 29, starting fromN-(4-cyano-3-trifluoromethyl-phenyl)-2,2,2-trifluoro-N-(2-methyl-acryloyl)-acetamideand 4-methyl-2-[(1E)-2,2,2-trifluoroethylidene]benznenesulfonylhydrazone, the title compound was prepared as a yellow solid.

¹H NMR (CDCl₃) δ8.10 (s, 1H), 7.95 (d, J=7.5 Hz, 1H), 7.60 (d, J=7.5 Hz,1H), 3.75 (d, J=10.5 Hz, 1H), 3.21 (d, J=10.5 Hz, 1H), 1.85 (s, 3H)

MS (m/z): MNa+ 483

EXAMPLE 1253-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-bromo-3-trifluoromethyl-phenyl)-amide Compound #119

Following the procedure described in Example 29, starting fromN-(4-bromo-3-trifluoromethyl-phenyl)-2-methyl-acrylamide and4-methyl-2-[(1E)-2,2,2-trifluoroethylidene]benznenesulfonyl hydrazone,the title compound was prepared as a yellow solid.

¹H NMR (CDCl₃) δ 8.95 (s, 1H), 7.96 (s, 1H), 7.65 (s, 2H), 5.86 (s, 1H),3.28 (abq, J=9.8 Hz, 1H), 3.10 (abq, J=9.8 Hz, 1H), 1.60 (s, 3H)

MS (m/z): MH⁺ 419.

EXAMPLE 1262-Ethyl-3-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylicacid (4-cyano-3-trifluoromethyl-phenyl)-amide Compound #120

andN-(4-Cyano-3-trifluoromethyl-phenyl)-3-methyl-5-trifluoromethyl-4,5-dihydro-3H-pyrazole-3-carboximidicacid ethyl ester Compound #200

3-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide (400 mg, 1.1 mmol) and Na₂HPO₄(1.0 g, 7 mmol) in CH₂Cl₂ (10 ml) was treated with BF₄.O(CH₂CH₃)₃ (1M inCH₂Cl₂, 5.0 ml) at 0° C. The reaction mixture was warmed to roomtemperature, stirred overnight and then quenched with NaHCO₃. CH₂Cl₂ wasadded to extract the product and the organic layer was then washed withbrine and dried over Na₂SO₄. Upon the purification on silica gel(CH₂Cl₂:ethyl acetate: 10:1), the title compounds were obtained as whitesolids.

2-Ethyl-3-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylicacid (4-cyano-3-trifluoromethyl-phenyl)-amide

¹H NMR (CDCl₃) δ 9.10 (br, 1H), 8.10 (s, 1H), 7.95 (m, 1H), 7.80 (m,1H), 3.40-3.00 (m, 4H), 1.50 (s, 3H), 1.35 (m, 3H)

MS (m/z): MH⁺ 393

N-(4-Cyano-3-trifluoromethyl-phenyl)-3-methyl-5-trifluoromethyl-4,5-dihydro-3H-pyrazole-3-carboximidicacid ethyl ester

¹H NMR (CDCl₃) δ 7.85 (m, 1H), 7.65 (s, 1H), 7.50 (s, 1H), 5.30 (m, 1H),4.40 (m, 1H), 3.90 (m, 1H), 2.95 (m, 1H), 2.40 (m, 1H), 1.55 (m, 3H),1.50 (s, 3H)

MS (m/z): MH⁺ 393

EXAMPLE 1272-Ethyl-3(R)-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylicacid (4-cyano-3-trifluoromethyl-phenyl)-amide Compound #125

andN-(4-Cyano-3-trifluoromethyl-phenyl)-3(R)-methyl-5-trifluoromethyl-4,5-dihydro-3H-pyrazole-3-carboximidicacid ethyl ester Compound #202

Following the procedure described in Example 126, starting from3(R)-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide, the title compounds wereprepared as off-white solids.

NMR and MS data of the title compounds were the same as described inExample 126.

EXAMPLE 1282-Ethyl-3(S)-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylicacid (4-cyano-3-trifluoromethyl-phenyl)-amide Compound #122

andN-(4-Cyano-3-trifluoromethyl-phenyl)-3(S)-methyl-5-trifluoromethyl-4,5-dihydro-3H-pyrazole-3-carboximidicacid ethyl ester Compound #201

Following the procedure described in Example 126, starting from3(S)-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide, the title compounds wereprepared as off-white solids.

NMR and MS data of the title compounds were the same as described inExample 126.

EXAMPLE 1292,3-Dimethyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide Compound #123

andN-(4-Cyano-3-trifluoromethyl-phenyl)-2,3-dimethyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboximidicacid methyl ester Compound #203

3-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide (2.5 mmoL) in DCM (25 mL) at 0°C. was treated with diethylpropyl amine (10 mmoL) followed by methyltriflate (2.5 mmoL). The reaction mixture was gradually warmed to roomtemperature and then stirred overnight. The reaction mixture waspartitioned between DCM and water. The DCM layer was washed withsaturated sodium bicarbonate, brine, then dried over anhydrous Na₂SO₄,filtered and concentrated to yield a yellow oil, which was then purifiedby column chromatography (silica gel, using ethyl acetate as eluent) toyield the title compounds as off-white solids.

2,3-Dimethyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide

¹H NMR (CDCl₃) δ 9.02 (s, 1H), 8.11 (s, 1H), 7.98 (d, J=7.5 Hz, 1H),7.82 (d, J=7.5 Hz, 1H), 3.32 (abq, J=9.5 Hz, 1H), 3.02 (abq, J=9.5 Hz,1H), 3.01 (s, 3H), 1.52 (s, 3H)

MS (m/z): MH⁺ 379.

N-(4-Cyano-3-trifluoromethyl-phenyl)-2,3-dimethyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboximidicacid methyl ester

¹H NMR (CDCl₃) δ 8.21 (s, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.90 (d, J=8.0Hz, 1H), 4.36 (s, 3H), 3.52 (s, 3H), 3.36 (d, J=12.5 Hz, 1H), 3.10 (d,J=12.5 Hz, 1H), 1.52 (s, 3H)

MS (m/z): MH⁺ 393.

EXAMPLE 1305-Chloro-3-methyl-5-trifluoromethyl-4,5-dihydro-3H-pyrazole-3-carboxylicacid (4-cyano-3-trifluoromethyl-phenyl)-amide Compound #124

3-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide (1.1 mmoL) in toluene (5 mL)was treated with PCl₅ (1.2 mmoL) at 100° C. for 2 hrs. The solvent wasremoved and the residue was purified by column chromatography usinghexanes and ethyl acetate as eluent to yield the title compound as awhite solid (3:2 diastereomers).

Major Diastereomer:

¹H NMR (CDCl₃) δ8.32 (s, 1H), 8.10 (s, 1H), 7.95 (d, J=7.5 Hz, 1H), 7.85(d, J=7.5 Hz, 1H), 3.05 (abq, J=9.8 Hz, 1H), 2.25 (abq, J=9.8 Hz, 1H),1.90 (s, 3H).

Minor Diastereomer

¹H NMR (CDCl₃) δ 8.62 (s, 1H), 8.11 (s, 1H), 7.96 (d, J=7.5 Hz, 1H),7.87 (d, J=7.5 Hz, 1H), 2.90 (abq, J=9.8 Hz, 1H), 2.32 (abq, J=9.8 Hz,1H), 1.88 (s, 3H).

MS, MH+, 399.

EXAMPLE 131N-(4-Cyano-2-iodo-5-trifluoromethyl-phenyl)-2-methyl-acrylamide

Following the procedure described in Example 1, starting from4-amino-5-iodo-2-trifluoromethyl-benzonitrile (known compound), thetitle compound was prepared as off-white solid.

¹H NMR (CDCl₃) δ 9.00 (s, 1H), 8.30 (br, 1H), 8.20 (s, 1H), 6.00 (s,1H), 5.65 (s, 1H), 2.15 (s, 3H)

MS (m/z): MH⁻ 379

EXAMPLE 1323-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-2-iodo-5-trifluoromethyl-phenyl)-amide Compound #126

Following the procedure described in Example 29, starting fromN-(4-cyano-2-iodo-5-trifluoromethyl-phenyl)-2-methyl-acrylamide, thetitle compound was prepared as an off-white solid.

¹H NMR (CDCl₃) δ 9.80 (s, 1H), 9.10 (s, 1H), 8.20 (s, 1H), 6.00 (s, 1H),3.25 and 3.10 (abq, J=14.5 Hz, 2H), 1.65 (s, 3H)

MS (m/z): MH⁺ 491.

EXAMPLE 133N-(4-Cyano-2-ethyl-3-trifluoromethyl-phenyl)-2-methyl-acrylamide

Following the procedure described in Example 1, starting from4-amino-2-ethyl-2-trifluoromethyl-benzonitrile (known compound), thetitle compound was prepared as an off-white solid.

¹H NMR (CDCl₃) δ 8.60 (d, J=8.5 Hz, 1H), 7.80 (s, 1H), 7.72 (d, J=8.5Hz, H), 5.88 (s, 1H), 5.63 (s, 1H), 2.85 (q, J=9.0 Hz, 2H), 2.12 (s,3H), 1.40 (t, J=9.0 Hz, 3H)

MS (m/z): MH⁺ 283.

EXAMPLE 1343-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-2-ethyl-3-trifluoromethyl-phenyl)-amide Compound #127

Following the procedure described in Example 29, starting fromN-(4-cyano-2-ethyl-3-trifluoromethyl-phenyl)-2-methyl-acrylamide, thetitle compound was prepared as an off-white solid.

¹H NMR (MeOD) δ 9.50 (s, 1H), 8.60 (d, J=1.8 Hz, 1H), 7.70 (d, J=1.8 Hz,1H), 5.90 (s, 1H), 3.30 and 3.05 (abq, J=12.0 Hz, 2H), 2.80 (m, 2H),1.65 (s, 3H), 1.20 (m, 3H)

MS (m/z): MH⁺ 393

EXAMPLE 135 4-Amino-5-ethyl-2-trifluoromethyl-benzonitrile

4-Amino-5-iodo-2-trifluoromethyl-benzonitrile (936 mg, 3.0 mmol), CuI(I) (57 mg, 0.3 mmol), PdCl₂(PPh₃)₂ (105.3 mg, 0.15 mmol), triethylamine(1.01 g, 10 mmol) and ethynyl-trimethyl-silane (450 mg, 4.5 mmol) weremixed in THF (30 ml). The reaction mixture was stirred at roomtemperature overnight. Tetrabutylammonium fluoride (1.0 M in THF, 3.0ml, 3.0 mmol) was added to the reaction mixture, which was then stirredat room temperature for 20 mins. The reaction mixture was quenched byaddition of H₂O and extracted with ethyl acetate. The organic layerswere combined and washed with brine, dried over Na₂SO₄ and concentratedto yield crude product 4-amino-5-ethynyl-2-trifluoromethyl-benzonitrile.

The crude product was mixed with Pd/C (0.3 g) in methanol (50 ml) withH₂ (40 psi). The reaction was shaken on a Parr shaker at roomtemperature overnight. Upon separation on silica gel (100% CH₂Cl₂), thetile compound was obtained in as a colorless liquid.

¹H NMR (CDCl₃) δ 7.50 (s, 1H), 7.00 (s, 1H), 4.50 (br, 2H), 2.50 (m,2H), 1.30 (m, 3H)

MS (m/z): MH⁺ 214

EXAMPLE 136N-(4-Cyano-2-ethyl-5-trifluoromethyl-phenyl)-2-methyl-acrylamide

Following the procedure described in Example 1, starting from4-amino-6-ethyl-2-trifluoromethyl-benzonitrile, the title compound wasprepared as an off-white solid.

¹H NMR (CDCl₃) δ 8.80 (s, 1H), 7.70 (br, 1H), 7.65 (s, 1H), 5.90 (s,1H), 5.60 (s, 1H), 3.70 (m, 2H), 2.10 (s, 3H), 1.30 (m, 3H)

MS (m/z): MH⁻ 283

EXAMPLE 1373-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-2-ethyl-5-trifluoromethyl-phenyl)-amide Compound #128

Following the procedure described in Example 29, starting fromN-(4-cyano-6-ethyl-3-trifluoromethyl-phenyl)-2-methyl-acrylamide, thetitle compound was prepared as an off-white solid.

¹H NMR (CDCl₃) δ 9.30 (s, 1H), 8.80 (s, 1H), 7.55 (s, 1H), 5.90 (s, 1H),3.25 and 3.10 (abq, J=14.0 Hz, 2H), 2.70 (m, 2H), 1.65 (s, 3H), 1.30 (m,3H)

MS (m/z): MH⁺ 393

EXAMPLE 138 4-Amino-6-trifluoromethyl-isophthalonitrile

4-Amino-5-iodo-2-trifluoromethyl-benzonitrile (1.5 mmoL), CuCN (1.7mmoL) in NMP (10 mL) was heated at 150° C. for 4 hrs. The reactionmixture was passed through a pad of Celite. The reaction mixture wasthen partitioned between ethyl acetate and water. The organic layer waswashed with water, then brine, dried over anhydrous Na₂SO₄, filtered andconcentrated to yield the title compound as a brown solid.

¹H NMR (CDCl₃) δ 7.82 (s, 1H), 7.15 (s, 1H), 5.45 (br, s, 2H)

MS (m/z): MH⁺ 212

EXAMPLE 139 N-(2,4-Dicyano-5-trifluoromethyl-phenyl)-2-methyl-acrylamide

Following the procedure described in Example 1, starting from4-amino-6-trifluoromethyl-isophthalonitrile, the title compound wasprepared as an off-white solid.

¹H NMR (CDCl₃) δ 9.15 (s, 1H), 8.45 (br, s, 1H), 8.08 (s, 1H), 6.05 (s,1H), 5.75 (s, 1H), 2.12 (s, 3H)

MS (m/z): MH⁺ 280

EXAMPLE 1403-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(2,4-dicyano-5-trifluoromethyl-phenyl)-amide Compound #129

Following the procedure described in Example 29, starting fromN-(2,4-dicyano-5-trifluoromethyl-phenyl)-2-methyl-acrylamide, the titlecompound was prepared as an off-white solid.

¹H NMR (CDCl₃) δ10.10 (s, 1H), 9.10 (s, 1H), 8.10 (s, 1H), 6.45 (s, 1H),3.30 and 3.10 (abq, J=14.0 Hz, 2H), 1.65 (s, 3H)

MS (m/z): MH⁺ 390

EXAMPLE 141 4-Amino-5-ethylsulfanyl-2-trifluoromethyl-benzonitrile

4-Amino-5-iodo-2-trifluoromethyl-benzonitrile (6.24 g, 20.0 mmol), CuI(I) (380 mg, 2.0 mmol), K₂CO₃ (6.52 g, 40.0 mmol) and ethylthiol (1.25g, 20.0 mmol) were mixed in ethanol (50 ml). The reaction mixture wasrefluxed overnight and then the solvent was removed under vacuum. Uponseparation on silica gel (100% DCM), the tile compound was obtained as acolorless liquid.

¹H NMR (CDCl₃) δ 7.70 (s, 1H), 7.00 (s, 1H), 5.10 (br, 2H), 2.85 (m,2H), 1.25 (m, 3H)

MS (m/z): MH₂O⁺ 264

EXAMPLE 142N-(4-Cyano-2-ethylsulfanyl-5-trifluoromethyl-phenyl)-2-methyl-acrylamide

Following the procedure described in Example 1, starting from4-amino-5-ethylsulfanyl-2-trifluoromethyl-benzonitrile, the titlecompound was prepared as an off-white solid.

¹H NMR (CDCl₃) δ 9.10 (br, s, 1H), 9.05 (s, 1H), 7.88 (s, 1H), 5.98 (s,1H), 5.60 (s, 1H), 2.95 (q, J=9.5 Hz, 2H), 2.12 (s, 3H), 1.32 (t, J=9.5Hz, 3H)

MS (m/z): MH⁺ 315

EXAMPLE 1433-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-2-ethylsulfanyl-5-trifluoromethyl-phenyl)-amide Compound #140

Following the procedure described in Example 29, starting fromN-(4-cyano-2-ethylsulfanyl-5-trifluoromethyl-phenyl)-2-methyl-acrylamide,the title compound was prepared as an off-white solid.

¹H NMR (CDCl₃) δ 8.30 (br, 1H), 7.35 (m, 1H), 7.10 (s, 1H), 6.80 (m,1H), 5.10 (br, 1H), 3.25 and 3.10 (abq, J=11.0 Hz, 2H), 1.60 (s, 3H)

MS (m/z): MH⁺ 365

EXAMPLE 1443-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-2-ethanesulfonyl-5-trifluoromethyl-phenyl)-amide Compound #142

3-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-2-ethylsulfanyl-5-trifluoromethyl-phenyl)-amide (150 mg, 0.35mmol) in ethyl acetate was treated with Oxone® (2.0 g, pH=7-8, adjustedwith saturated NaHCO₃ and tetrabuylammonium hydrogensulfate (30 mg). Thereaction mixture was stirred at room temperature overnight and thenquenched with saturated NaHCO₃. The crude product was extracted withethyl acetate twice, washed with brine and dried with Na₂SO₄. Uponpurification on silica gel (CH₂Cl₂:EtOAc: 3:1), the title compound wasobtained as a white solid.

¹H NMR (CDCl₃) δ 9.20 (s, 1H), 8.30 (s, 1H), 6.05 (s, 1H), 3.25 and 3.10(abq, J=12.0 Hz, 2H), 3.15 (m, 2H), 1.65 (s, 3H), 1.30 (m, 3H). MS (m/z)

MH⁺ 457

EXAMPLE 145 4-Amino-5-tert-butylsulfanyl-2-trifluoromethyl-benzonitrile

Following the procedure described in Example 141, starting from t-butylthiol, the title compound was prepared as a brown solid.

¹H NMR (CDCl₃) δ 7.75 (s, 1H), 7.00 (s, 1H), 5.45 (br, 2H), 1.30 (s, 9H)

MS (m/z): MH₂O 292

EXAMPLE 146N-(2-tert-Butylsulfanyl-4-cyano-5-trifluoromethyl-phenyl)-2-methyl-acrylamide

Following the procedure described in Example 1, starting from4-amino-5-tert-butylsulfanyl-2-trifluoromethyl-benzonitrile, the titlecompound was prepared as an off-white solid.

¹H NMR (CDCl₃) δ 9.65 (s, 1H), 9.15 (s, 1H), 7.95 (s, 1H), 6.00 (s, 1H),5.65 (s, 1H), 2.10 (s, 3H), 1.35 (s, 9H)

MS (m/z): MH⁻ 341

EXAMPLE 1473-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(2-tert-butylsulfanyl-4-cyano-5-trifluoromethyl-phenyl)-amide Compound#143

Following the procedure described in Example 29, starting fromN-(2-tert-butylsulfanyl-4-cyano-5-trifluoromethyl-phenyl)-2-methyl-acrylamide,the title compound was prepared as an off-white solid.

¹H NMR (CDCl₃) δ10.75 (s, 1H), 9.10 (s, 1H), 7.95 (s, 1H), 6.00 (s, 1H),3.20 and 3.05 (abq, J=11.0 Hz, 2H), 1.65 (s, 3H), 1.30 (s, 9H)

MS (m/z): MH⁻ 452

EXAMPLE 148 4-Amino-5-methoxy-2-trifluoromethyl-benzonitrile

4-Amino-5-iodo-2-trifluoromethyl-benzonitrile (312 mg, 1.0 mmol), CuI(I) (20 mg, 0.1 mmol), Cs₂CO₃ (652 mg, 2.0 mmol) and 1,10-phenanthroline(36 mg, 0.2 mmol) were mixed in methanol (20 ml). The reaction mixturewas refluxed overnight and then the solvent was removed under vacuum.Upon separation on silica gel (100% CH₂Cl₂), the tile compound wasobtained as a colorless liquid.

¹H NMR (CDCl₃) δ 7.05 (s, 1H), 6.90 (s, 1H), 4.50 (br, 2H), 3.90 (s, 3H)

MS (m/z): MH⁺ 216

EXAMPLE 149N-(4-Cyano-2-methoxy-5-trifluoromethyl-phenyl)-2-methyl-acrylamide

Following the procedure described in Example 1, starting from4-amino-5-methoxy-2-trifluoromethyl-benzonitrile, the title compound wasprepared as an off-white solid.

¹H NMR (CDCl₃) δ 9.00 (s, 1H), 8.40 (s, 1H), 7.26 (s, 1H), 5.90 (s, 1H),5.60 (s, 1H), 4.00 (s, 3H), 2.10 (s, 3H)

EXAMPLE 1503-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-2-methoxy-5-trifluoromethyl-phenyl)-amide Compound #141

Following the procedure described in Example 29, starting fromN-(4-cyano-2-methoxy-5-trifluoromethyl-phenyl)-2-methyl-acrylamide, thetitle compound was prepared as an off-white solid.

¹H NMR (CDCl₃) δ 9.65 (br, 1H), 8.90 (s, 1H), 7.25 (s, 1H), 5.90 (s,1H), 4.00 (s, 3H), 3.25 and 3.05 (abq, J=10.0 Hz, 2H), 1.60 (s, 3H)

MS (m/z): MH⁺ 395

EXAMPLE 151 4-Amino-5-chloro-2-trifluoromethyl-benzonitrile

and 4-Amino-3,5-dichloro-2-trifluoromethyl-benzonitrile

4-Amino-2-trifluoromethyl-benzonitrile (10.5 mmoL), NCS (15.5 mmoL) inMeOH (50 mL) at 0° C. was stirred for 2 hrs. The solvent was removed andthe residue was partitioned between ethyl acetate and water. The organiclayer was washed with sodium thiosulfate, water and brine, then driedover anhydrous Na₂SO₄, filtered and concentrated to yield crudematerial, which was then purified by column chromatography using hexanesand ethyl acetate to yield the title compounds as brown solids.

4-Amino-5-chloro-2-trifluoromethyl-benzonitrile

H NMR (CDCl₃) δ 7.65 (s, 1H), 7.02 (s, 1H), 4.90 (br, s, 2H)

MS (m/z): MH⁺ 221.

4-Amino-3,5-dichloro-2-trifluoromethyl-benzonitrile

¹H NMR (CDCl₃) δ 7.61 (s, 1H), 5.32 (br, s, 2H)

MS (m/z): MH⁺ 256.

EXAMPLE 152N-(2-Chloro-4-cyano-5-trifluoromethyl-phenyl)-2-methyl-acrylamide

Following the procedure described in Example 1, starting from4-amino-5-chloro-2-trifluoromethyl-benzonitrile, the title compound wasprepared as an off-white solid.

¹H NMR (CDCl₃) δ 7.95 (s, 1H), 7.52 (s, 1H), 5.80 (br, s, 1H), 5.65 (s,1H), 5.60 (s, 1H)

MS (m/z): MH⁺ 289

EXAMPLE 1533-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(2-chloro-4-cyano-5-trifluoromethyl-phenyl)-amide Compound #130

Following the procedure described in Example 29, starting fromN-(2-chloro-4-cyano-5-trifluoromethyl-phenyl)-2-methyl-acrylamide, thetitle compound was prepared as an off-white solid.

¹H NMR (CDCl₃) δ 9.88 (br, s, 1H), 9.05 (s, 1H), 7.90 (s, 1H), 3.31(abq, J=10.5 Hz, 1H), 3.15 (abq, J=11.0 Hz, 1H), 1.68 (s, 3H)

MS (m/z): MH⁺ 399

EXAMPLE 154N-(2,6-Dichloro-4-cyano-3-trifluoromethyl-phenyl)-2-methyl-acrylamide

Following the procedure described in Example 1, starting from4-amino-3,5-dichloro-2-trifluoromethyl-benzonitrile, the title compoundwas prepared as an off-white solid.

¹H NMR (CDCl₃) δ 7.88 (s, 1H), 7.50 (s, 1H), 6.02 (s, 1H), 5.68 (s, 1H),2.11 (s, 3H)

MS (m/z): MH⁺ 324

EXAMPLE 1553-Methyl-5-trifluoromethyl-4,5-dihydro-3H-pyrazole-3-carboxylic acid(2,6-dichloro-4-cyano-3-trifluoromethyl-phenyl)-amide Compound #137

and 3-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(2,6-dichloro-4-cyano-3-trifluoromethyl-phenyl)-amide Compound #139

and 3-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(2,6-dichloro-4-cyano-3-trifluoromethyl-phenyl)-(2,2,2-trifluoro-ethyl)-amideCompound #138

Following the procedure described in Example 29, starting fromN-(2,6-dichloro-4-cyano-3-trifluoromethyl-phenyl)-2-methyl-acrylamide,the title compounds were prepared as off-white solids.

3-Methyl-5-trifluoromethyl-4,5-dihydro-3H-pyrazole-3-carboxylic acid(2,6-dichloro-4-cyano-3-trifluoromethyl-phenyl)-amide

¹H NMR (CDCl₃) δ 8.82 (s, 1H), 7.71 (s, 1H), 3.70 (m, 1H), 3.60 (m, 1H),2.85 (m, 1H), 1.35 (s, 3H)

MS (m/z): MH⁺ 434.

3-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(2,6-dichloro-4-cyano-3-trifluoromethyl-phenyl)-amide

¹H NMR (CDCl₃) δ 9.08 (s, 1H), 7.50 (s, 1H), 5.72 (s, 1H), 3.25 (abq,J=10.5 Hz, 1H), 2.85 (abq, J=10.5 Hz, 1H), 1.58 (s, 3H)

MS (m/z): MH⁺ 434.

3-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(2,6-dichloro-4-cyano-3-trifluoromethyl-phenyl)-(2,2,2-trifluoro-ethyl)-amide

¹H NMR (CDCl₃) δ 7.88 (s, 1H), 5.62 (m, 1H), 3.75 (m, 2H), 3.58 (abq,J=12.5 Hz, 1H), 2.92 (abq, J=12.5 Hz, 1H), 1.68 (s, 3H)

MS (m/z): MH⁺ 516

EXAMPLE 1563-Methyl-2-(2,2,2-trifluoro-acetyl)-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylicacid (4-cyano-3-trifluoromethyl-phenyl)-amide Compound #131

3-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide (1.5 mmoL) in DCM (˜20 mL) wasreacted with pyridine (2.0 mmoL) followed by trifluoroacetic anhydride(1.5 mmoL) which was added dropwise at 0° C. The reaction mixture wasthen stirred for 2 hrs. The solvent was removed and the residue waspartitioned between DCM and water. The organic layer was washed withsaturated sodium bicarbonate, water and then brine, dried over anhydrousNa₂SO₄, filtered and concentrated to yield crude material, which wasthen purified by column chromatography using hexanes and ethyl acetateto yield the title compound as an off-white solid.

¹H NMR (CDCl₃) δ 9.72 (s, 1H), 8.08 (s, 1H), 7.88 (d, J=8.5 Hz, 1H),7.80 (d, J=8.5 Hz, 1H), 4.35 (abq, J=12.5 Hz, 1H), 3.10 (abq, J=12.5 Hz,1H), 2.01 (s, 3H)

MS (m/z): MH⁺ 461

EXAMPLE 1572-Ethyl-3-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylicacid (4-cyano-3-trifluoromethyl-phenyl)-methyl-amide Compound #123

2-Ethyl-3-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylicacid (4-cyano-3-trifluoromethyl-phenyl)-amide (1.1 mmoL) in DMF (10 mL)was treated with NaH (60%, 1.2 mmoL) followed by CH₃I (1.1 mmoL) at 0°C. The reaction mixture was stirred for 1 hr and then warmed to roomtemperature. The reaction mixture was then partitioned between diethylether and water. The organic layer was washed with saturated sodiumbicarbonate, water and then brine, dried over anhydrous Na₂SO₄, filteredand concentrated to yield crude material, which was then purified bycolumn chromatography using hexanes and ethyl acetate to yield the titlecompound as an off-white solid.

¹H NMR (CDCl₃) δ 7.80 (m, 1H), 7.60 (s, 1H), 7.45 (m, 1H), 3.40 (s, 3H),3.35 and 2.90 (abq, J=14.0 Hz, 2H), 3.20 (m, 1H), 3.00 (m, 1H), 1.50 (s,3H), 1.15 (t, J=3.0 Hz, 3H)

MS (m/z): MH⁺ 390

EXAMPLE 158 3,5-Dimethyl-4,5-dihydro-isoxazole-5-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide Compound #134

Following the procedure described in Example 27, starting fromacetaldehyde oxime, the title compound was prepared as an off-whitesolid.

¹H NMR (CDCl₃) δ 8.65 (s, 1H), 7.95 (s, 1H), 7.40 (m, 2H), 3.40 and 2.95(abq, J=14.0 Hz, 2H), 2.00 (s, 3H), 1.70 (s, 3H)

MS (m/z): MH⁺ 390

EXAMPLE 1593-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carbothioic acid(4-cyano-3-trifluoromethyl-phenyl)-amide Compound #118

3-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide (15 mmoL) and Lawesson's agent(15 mmoL) in toluene (100 mL) was refluxed for 6 hrs until the solutionturned clear. The reaction mixture was then cooled and some precipitatewas observed. The solid was removed by filtration and the filtrate wasconcentrated to yield crude product as a green oil. The green oil waspurified by silica gel column chromatography using DCM and ethyl acetateas eluent to yield the title compound as a green solid.

¹H NMR (CDCl₃) δ 11.05 (s, 1H), 8.45 (s, 1H), 8.30 (d, J=8.5 Hz, 1H),7.82 (d, J=8.5 Hz, 1H), 5.95 (br, s, 1H), 3.40 (abq, J=9.5 Hz, 1H), 3.21(abq, J=9.5 Hz, 1H), 1.85 (s, 3H)

MS (m/z): MH⁺ 381

EXAMPLE 160N-(4-Cyano-3-trifluoromethyl-phenyl)-3-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboximidothioicacid ethyl ester Compound #204

3-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carbothioic acid(4-cyano-3-trifluoromethyl-phenyl)-amide (10 mmoL), K₂CO₃ (15 mmoL) inacetone was treated with CH₃CH₂₁ (10 mmoL) at room temperature. Thereaction mixture was heated gently and then stirred at 50° C. for 1 hr.The solid was filtrated and the filtrate was concentrated to yield crudeproduct as a brown oil, which was then purified by silica gel columnchromatography using hexanes and ethyl acetate as eluent to yield thetitle compound as a colorless oil.

¹H NMR (CDCl₃) δ7.80 (d, J=7.8 Hz, 1H), 7.28 (s, 1H), 7.15 (d, J=7.9 Hz,1H), 6.50 (s, 1H), 3.51 (abq, J=12.5 Hz, 1H), 2.88 (abq, J=12.5 Hz, 1H),2.35 (q, J=8.5 Hz, 2H), 1.08 (t, J=8.5 Hz, 3H)

MS (m/z): MH⁺ 409

EXAMPLE 161N-(4-Cyano-3-trifluoromethyl-phenyl)-N′-ethyl-3-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxamidineor its tautomerN-(4-Cyano-3-trifluoromethyl-phenyl)-N′-ethyl-3-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxamidineCompound #205 or its Tautomer

N-(4-Cyano-3-trifluoromethyl-phenyl)-3-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboximidothioicacid ethyl ester (2 mmoL) in dioxane (15 mL) was treated with ethylamine/THF solution (˜3 mmoL) and K₂CO₃ (2 mmoL) at 70° C. The reactionmixture was then stirred 4 hr. The solid was removed by filtration. Thefiltrate was concentrated to yield crude product, which was thenpurified by silica gel column chromatography using hexanes and ethylacetate as eluent to yield the title compound as a white solid.

¹H NMR (CDCl₃) δ 7.62 (d, J=7.5 Hz, 1H), 7.10 (s, 1H), 6.95 (d, J=7.5Hz, 1H), 6.15 (s, 1H), 5.78 (s, 1H), 3.20 (abq, J=9.5 Hz, 1H), 2.95(abq, J=9.5 Hz, 1H), 2.85 (q, J=8.0 Hz, 2H), 1.48 (s, 3H), 1.30 (t,J=8.0 Hz, 3H)

MS (m/z): MH⁺ 392

EXAMPLE 162N-(4-Cyano-3-trifluoromethyl-phenyl)-N′-hydroxy-3-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxamidineor its tautomerN-(4-Cyano-3-trifluoromethyl-phenyl)-N′-hydroxy-3-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxamidineCompound #206 or its Tautomer

N-(4-Cyano-3-trifluoromethyl-phenyl)-3-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboximidothioicacid ethyl ester (1 mmoL) in DMF (5 mL) was treated with N-hydroxaminehydrochloride salt (1 mmoL) and K₂CO₃ (2 mmoL) at room temperature. Thereaction mixture was then stirred for 4 hr. The solid was removed byfiltration. The filtrate was partitioned between ethyl acetate andwater. The organic layer was dried over anhydrous sodium sulfate,filtrated and concentrated to yield crude product, which was thenpurified by silica gel column chromatography using hexanes and ethylacetate as eluent to yield the title compound as a white solid.

¹H NMR (CDCl₃) δ 8.20 (s, 1H), 7.62 (d, J=7.5 Hz, 1H), 7.05 (s, 1H),6.85 (d, J=7.5 Hz, 1H), 5.92 (s, 1H), 3.25 (abq, J=8.8 Hz, 1H), 2.82(abq, J=8.8 Hz, 1H), 1.50 (s, 3H)

MS (m/z): MH⁺ 380

EXAMPLE 163N-(4-Cyano-3-trifluoromethyl-phenyl)-N′-methoxy-3-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxamidineor its tautomerN-(4-Cyano-3-trifluoromethyl-phenyl)-N′-methoxy-3-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxamidineCompound #210 or its Tautomer

Following the procedure described in Example 162, starting fromO-methyl-hydroxylamine andN-(4-Cyano-3-trifluoromethyl-phenyl)-3-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboximidothioicacid ethyl ester, the title compound was prepared as an off-white solid.

¹H NMR (CDCl₃) δ 7.72 (d, J=6.5 Hz, 1H), 7.22 (s, 1H), 7.11 (d, J=6.5Hz, 1H), 6.12 (s, 1H), 3.60 (s, 3H), 3.50 (abq, J=8.5 Hz, 1H), 2.95(abq, J=8.5 Hz, 1H), 1.58 (s, 3H)

MS (m/z): MH⁺ 394

EXAMPLE 164N-(4-Cyano-3-trifluoromethyl-phenyl)-3-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxamidineor its tautomerN-(4-Cyano-3-trifluoromethyl-phenyl)-3-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxamidineCompound #207 or its Tautomer

andN-(4-Cyano-3-trifluoromethyl-phenyl)-3-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboximidicacid methyl ester Compound #212

N-(4-Cyano-3-trifluoromethyl-phenyl)-3-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboximidothioicacid ethyl ester (1.2 mmoL) in dioxane (10 mL) was treated with ammoniain MeOH (7N solution, ˜10 mL) in a sealed tube. The reaction mixture washeated to 100° C. for 4 hrs. The solvent was removed and the residue waspurified by silica gel column chromatography using ethyl acetate andmethanol as eluent to yield the title compounds as white solids.

N-(4-Cyano-3-trifluoromethyl-phenyl)-3-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxamidine

¹H NMR (CDCl₃) δ 9.50 (br, s, 1H), 8.11 (s, 1H), 7.95 (d, J=7.5 Hz, 1H),7.78 (d, J=7.5 Hz, 1H), 5.63 (s, 1H), 3.05 (abq, J=10.5 Hz, 1H), 2.95(abq, J=10.5 Hz, 1H), 1.58 (s, 3H)

MS (m/z): MH⁺ 364.

N-(4-Cyano-3-trifluoromethyl-phenyl)-3-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboximidicacid methyl ester

MS (m/z): MH⁺ 379.

EXAMPLE 165N-(4-Cyano-3-trifluoromethyl-phenyl)-3,N′-dimethyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxamidineor its tautomerN-(4-Cyano-3-trifluoromethyl-phenyl)-3,N′-dimethyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxamidineCompound #211 or its Tautomer

Following the procedure described in Example 164, starting from methylamine andN-(4-cyano-3-trifluoromethyl-phenyl)-3-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboximidothioicacid ethyl ester, the title compound was prepared as an off-white solid.

¹H NMR (CDCl₃) δ 7.60 (d, J=8.5 Hz, 1H), 7.00 (s, 1H), 6.90 (d, J=8.5Hz, 1H), 6.05 (s, 1H), 5.60 (s, 1H), 3.15 (abq, J=10.5 Hz, 1H), 2.85(abq, J=10.5 Hz, 1H), 2.90 (s, 3H), 1.45 (s, 3H)

MS (m/z): MH⁺ 378

EXAMPLE 166N′-(4-Cyano-3-trifluoromethyl-phenyl)-N,N-diethyl-3-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxamidineCompound #208

Following the procedure described in Example 164, starting from diethylamine andN-(4-cyano-3-trifluoromethyl-phenyl)-3-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboximidothioicacid ethyl ester, the title compound was prepared as an off-white solid.

¹H NMR (CDCl₃) δ 7.72 (d, J=7.5 Hz, 1H), 7.21 (s, 1H), 7.10 (d, J=7.5Hz, 1H), 6.31 (s, 1H), 3.70 (q, J=5.5 Hz, 1H), 3.55 (abq, J=10.5 Hz,1H), 3.45 (q, J=5.5 Hz, 1H), 3.05 (abq, J=10.5 Hz, 1H), 1.55 (s, 3H),1.20 (t, J=8.5 Hz, 6H)

MS (m/z): MH⁺ 420

EXAMPLE 1674-{[(3-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazol-3-yl)-pyrrolidin-1-yl-methylene]-amino}-2-trifluoromethyl-benzonitrileCompound #209

Following the procedure described in Example 164, starting frompyrrolidine andN-(4-cyano-3-trifluoromethyl-phenyl)-3-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboximidothioicacid ethyl ester, the title compound was prepared as an off-white solid.

¹H NMR (CDCl₃) δ 7.71 (d, J=7.0 Hz, 1H), 7.22 (s, 1H), 7.08 (d, J=7.0Hz, 1H), 3.77 (t, J=6.0 Hz, 1H), 3.62 (t, J=6.0 Hz, 1H), 3.60 (abq,J=9.5 Hz, 1H), 3.05 (abq, J=9.5 Hz, 1H), 1.95˜1.70 (m, 4H), 1.58 (s, 3H)

MS (m/z): MH⁺ 418

EXAMPLE 169N-[(4-Cyano-3-trifluoromethyl-phenylimino)-(3-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazol-3-yl)-methyl]-methanesulfonamideor its tautomerN-[(4-Cyano-3-trifluoromethyl-phenylamino)-(3-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazol-3-yl)-methylene]-methanesulfonamideCompound #214 or its Tautomer

Following the procedure described in Example 164, starting frommethylsulfonamide andN-(4-cyano-3-trifluoromethyl-phenyl)-3-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboximidothioicacid ethyl ester, the title compound was prepared as an off-white solid.

¹H NMR (CDCl₃) δ 7.85 (br, s, 1H), 7.75 (d, J=7.5 Hz, 1H), 7.58 (s, 1H),7.20 (d, J=7.5 Hz, 1H), 7.05 (br, s, 1H), 3.62 (abq, J=10.5 Hz, 1H),3.32 (abq, J=10.5 Hz, 1H), 1.61 9s, 3H)

MS (m/z): MH⁺ 442

EXAMPLE 1695-Nitro-2-[(3-methyl-3,4-dihydro-2H-pyrazole-3-carbonyl)-amino]-benzoicacid methyl ester Compound #147

Following the procedure described in Example 29, starting from5-nitro-2-(2-methyl-acryloylamino)-benzoic acid methyl ester, the titlecompound was prepared as an off-white solid.

¹H NMR (CDCl₃) δ 8.95 (d, J=7.5 Hz, 1H), 8.90 (s, 1H), 8.48 (d, J=7.5Hz, 1H), 6.80 (s, 1H), 5.61 (s, 1H), 4.01 (s, 3H), 3.10 (abq, J=10.5 Hz,1H), 2.90 (abq, J=10.5 Hz, 1H), 1.55 (s, 3H)

MS (m/z): MH⁺ 307

EXAMPLE 1703-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carbothioic acid(3,4-dichloro-phenyl)-amide Compound #136

Following the procedure described in Example 159, starting from3-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(3,4-dichloro-phenyl)-amide, the title compound was prepared as a greenoil.

¹H NMR (CDCl₃) δ10.70 (s, 1H), 8.10 (s, 1H), 7.65 (m, 1H), 7.45 (m, 1H),5.80 (s, 1H), 3.30 and 3.15 (abq, J=13.0 Hz, 2H), 1.80 (s, 3H)

MS (m/z): MH⁺ 357

EXAMPLE 171N-(3,4-Dichloro-phenyl)-3-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboximidothioicacid ethyl ester Compound #213

Following the procedure described in Example 160, starting from3-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carbothioic acid(3,4-dichloro-phenyl)-amide, the title compound was prepared as acolorless oil.

¹H NMR (CDCl₃) δ 7.40 (m, 1H), 7.00 (s, 1H), 6.80 (m, 1H), 6.60 (br,1H), 5.30 (s, 1H), 3.50 and 2.80 (abq, J=14.0 Hz, 2H), 2.30 (m, 2H),1.60 (s, 3H), 1.00 (m, 3H)

MS (m/z): MH⁺ 385

EXAMPLE 172

3(R)-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carbothioic acid(4-cyano-3-trifluoromethyl-phenyl)-amide

Compound #144

Following the procedure described in Example 159, starting from3(R)-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(3-trifluoromethyl-4-cyano-phenyl)-amide, the title compound wasprepared as a green oil.

NMR and MS data are the same as described in Example 159.

EXAMPLE 173N-(4-Cyano-3-trifluoromethyl-phenyl)-3(R)-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboximidothioicacid ethyl ester Compound #215

Following the procedure described in Example 160, starting from3(R)-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carbothioic acid(4-cyano-3-trifluoromethyl-phenyl)-amide, the title compound wasprepared as a colorless oil.

NMR and MS data are the same as described in Example 160.

EXAMPLE 1743(S)-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carbothioic acid(4-cyano-3-trifluoromethyl-phenyl)-amide Compound #145

Following the procedure described in Example 159, starting from3(S)-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(3-trifluoromethyl-4-cyano-phenyl)-amide, the title compound wasprepared as a green oil.

NMR and MS data are the same as described in Example 159.

EXAMPLE 175N-(4-Cyano-3-trifluoromethyl-phenyl)-3(S)-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboximidothioicacid ethyl ester Compound #216

Following the procedure described in Example 160, starting from3-(S)-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carbothioicacid (4-cyano-3-trifluoromethyl-phenyl)-amide, the title compound wasprepared as a colorless oil.

NMR and MS data are the same as described in Example 160.

EXAMPLE 176N-(4-Cyano-3-trifluoromethyl-phenyl)-2-ethyl-3(S)-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboximidothioicacid ethyl ester Compound #218

Following the procedure described in Example 126, starting fromN-(4-cyano-3-trifluoromethyl-phenyl)-3(S)-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboximidothioicacid ethyl ester, the title compound was prepared as a colorless oil.

¹H NMR (CDCl₃) δ 7.75 (d, J=7.5 Hz, 1H), 7.20 (s, 1H), 7.08 (D, j=7.5Hz, 1H), 3.50 (m, 2H), 3.28 (abq, J=12.5 Hz, 1H), 2.85 (abq, J=12.5 hz,1H), 2.48 (m, 2H), 1.50 (s, 3H), 1.35 (t, J=9.5 Hz, 3H), 1.28 (t, J=9.5Hz, 3H)

MS (m/z): MH⁺ 437

EXAMPLE 177N-(4-Cyano-3-trifluoromethyl-phenyl)-N′-cyano-2-ethyl-3(S)-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxamidineor its tautomerN′-cyano-N-[4-cyano-3-(trifluoromethyl)phenyl]-1-ethyl-4,5-dihydro-5(S)-methyl-3-(trifluoromethyl)-H-pyrazole-5-carboximidamideCompound #217 or its Tautomer

N-(4-Cyano-3-trifluoromethyl-phenyl)-2-ethyl-3-(S)-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboximidothioicacid ethyl ester (0.7 mmoL) in dioxane (5 mL) was treated with K₂CO₃(1.4 mmoL) and NH₂CN (1.0 mmoL) at 80° C. for 2 hr. The reaction mixturewas then filtrated through a pad of Celite. The filtrate wasconcentrated and purified by silica gel column chromatography usinghexanes and ethyl acetate as eluent to yield the title compound as awhite solid.

¹H NMR (CDCl₃) δ 9.25 (br, s, 1H), 8.05 (s, 1H), 8.01 (d, J=7.5 Hz, 1H),7.85 (d, J=7.5 Hz, 1H), 3.40 (abq, J=11.5 Hz, 2H), 3.28 (m, 1H), 3.05(m, 1H), 1.90 (s, 3H), 1.55 (t, J=85 Hz, 3H)

MS (m/z): MH⁺ 417

EXAMPLE 178 4-Methyl-2-trifluoromethyl-4,5-dihydro-oxazole-4-carboxylicacid (4-cyano-3-trifluoromethyl-phenyl)-amide Compound #110

3-Hydroxy-2-methyl-2-(2,2,2-trifluoro-acetylamino)-propionic acid (3.2mmoL) in DMA (10 mL) was treated dropwise with thionyl chloride (4.5mmoL) at 0° C. for 30 min. To the resulting solution was added4-amino-2-trifluoromethyl-benzonitrile (3.2 mmoL) in DMA (5 mL) followedby TEA (5 mmoL). The reaction mixture was slowly warmed to roomtemperature and stirred overnight. The reaction mixture was thenpartitioned between ethyl acetate and water. The organic layer waswashed with saturated sodium bicarbonate, then brine, dried overanhydrous sodium sulfate, filtrated and concentrated to yield crudeproduct, which was then purified by silica gel column chromatographyusing hexanes and ethyl acetate as eluent to yield the title compound asa white solid.

¹H NMR (CDCl₃) δ 8.62 (s, 1H), 8.05 (s, 1H), 8.13 (d, J=6.8 Hz, 1H),7.32 (d, J=6.8 Hz, 1H), 4.65 (abq, J=8.5 Hz, 1H), 4.45 (abq, J=8.5 Hz,1H), 1.55 (s, 3H)

EXAMPLE 179 4-Methyl-2-oxo-oxazolidine-4-carboxylic acid(4-cyano-3-trifluoromethyl-phenyl)-amide Compound #111

Following the procedure described in Example 178, starting from2-tert-butoxycarbonylamino-3-hydroxy-2-methyl-propionic acid (preparedby literature known method), the title compound was prepared as a whitesolid.

¹H NMR (CDCl₃) δ 8.31 (br, s, 1H), 8.05 (s, 1H), 7.95 (d, J=8.5 Hz, 1H),7.72 (d, J=8.5 Hz, 1H), 6.01 (s, 1H), 4.65 (d, J=8.0 Hz, 1H), 4.23 (d,J=8.0 Hz, 1H), 1.68 (s, 3H)

MS (m/z): MH⁺ 314

EXAMPLE 180 Ventral Prostate and Levator ani Weight in vivo Assay

Mature (150 to 200 g) castrated male Sprague Dawley rats (Charles River)were treated once daily for 14 days with test compound (usuallyadministered by oral gavage at up to the desired dosage, up to 30 mg/kgin a volume of 1 mL, in 30% cyclodextrin or 0.5% methylcellulosevehicle), or with testosterone propionate (administered subcutaneouslyby injection at the nape of the neck at 5 mg/kg, in a volume of 0.1 mLin sesame oil), or with vehicle (1 mL of 30% cyclodextrin or 0.5%methylcellulose, given orally). On the fifteenth day, the rats wereeuthanized by asphyxiation in carbon dioxide. Ventral prostates andlevator ani muscles were removed and their wet weights determined.

Test compound activity was determined as the percent stimulation oftissue weight, with the vehicle-treated control group set to zeropercent and the testosterone alone-treated control group set to 100%. Acompound was designated as agonist active if it produced greater than orequal to 20% stimulation of levator ani at 30 mg/kg.

Representative compounds of the present invention were tested accordingto the procedure described, with results as listed in Table 10 below.For the compounds listed in Table 10 as “inactive”, one skilled in theart will recognize that said compounds may or may not have shown aneffect on prostate and/or vesical weight, rather they are listed hereinas “inactive” as they did not meet the specified criteria defined above.A designation of “toxic” indicates that the compound exhibited toxicityin the rats tested.

TABLE 10 % Prostate % levator ani ID # Stimulation Stimulation 8 activeactive 9 inactive inactive 11 inactive inactive 15 inactive inactive 17inactive inactive 27 inactive inactive 30 inactive active 33 inactiveactive 34 inactive inactive 35 active active 36 inactive active 37inactive active 38 inactive inactive 39 inactive inactive 40 inactiveinactive 41 inactive inactive 43 inactive active 44 inactive inactive 45inactive inactive 46 inactive inactive 47 inactive inactive 48 inactiveinactive 73 inactive inactive 74 active active 75 inactive inactive 76inactive inactive 77 inactive inactive 78 inactive inactive 79 inactiveinactive 83 inactive inactive 84 inactive inactive 85 inactive active 86inactive active 87 active active 89 inactive inactive 90 inactiveinactive 91 inactive inactive 92 inactive inactive 98 active active 99active active 100 inactive active 102 inactive inactive 107 inactiveinactive 110 active inactive 111 inactive inactive 112 inactive active113 inactive inactive 114 inactive inactive 115 inactive inactive 116active active 118 toxic toxic 119 inactive active 120 active active 123inactive active 124 active active 125 active active 126 active active127 active active 128 inactive inactive 129 inactive inactive 130 activeactive 133 inactive active 134 inactive inactive 138 inactive inactive139 inactive inactive 140 inactive active 142 inactive inactive 202active active 205 inactive active 206 active active 207 active active208 active active 209 inactive inactive 210 inactive active 211 inactiveinactive 212 active active 214 inactive inactive 215 inactive inactive217 inactive inactive 218 active active

EXAMPLE 181 Ventral Prostate and Seminal Vesicle Weight In Vivo Assay

Immature (approximately 50 g) castrated male Sprague Dawley rats(Charles River) were treated once daily for five days with test compound(usually given orally at 40 mg/kg in a volume of 0.3 mL, in 30%cyclodextrin or 0.5% methylcellulose vehicle) and with testosteronepropionate (given subcutaneously by injection at the nape of the neck at2 mg/kg, in a volume of 0.1 mL in sesame oil). On the sixth day, therats were euthanized by asphyxiation in carbon dioxide. Ventralprosatates and seminal vesicles were removed and their wet weightsdetermined. Test compound activity was determined as the percentinhibition of testosterone-enhanced tissue weights, with avehicle-treated control group set to zero percent and a testosteronealone-treated control group set to 100%.

A test compound was said to be “active” if the non weight adjustedprostate weight was ≦40 mg or the % Inhibition prostate weight, bodyweight adjusted was ≧60% @ 2 mg/day dosage. ID₅₀'s, if determined, of≦20 mg/day also indicated an active compound.

Representative compounds of the present invention were tested accordingto the procedure described, with results as listed in Table 11 below.For the compounds listed in Table 11 as “inactive”, one skilled in theart will recognize that said compounds may or may not have shown aneffect on prostate and/or vesical weight, rather they are listed hereinas “inactive” as they did not meet the specified criteria defined above.

TABLE 11 Inhibition of prostate Inhibition of seminal vesicle(non-weight prostate (non-weight seminal vesicle ID # weight, mg)weight, mg) 1 active active 2 active active 3 active active 4 activeactive 5 active active 6 active active 7 active inactive 8 activeinactive 9 active inactive 10 active active 11 inactive inactive 12inactive inactive 13 active active 14 active active 15 inactive inactive24 inactive inactive 25 active active 42 active active 49 active active112 inactive inactive 113 inactive inactive 120 active active 124inactive inactive 127 active active 128 active active 129 inactiveinactive 133 inactive active 138 inactive inactive 139 active active 140inactive inactive 141 inactive inactive 142 inactive active 143 inactiveinactive 205 active active 214 inactive inactive

EXAMPLE 182

As a specific embodiment of an oral composition, 100 mg of the compoundprepared as in Example 95 is formulated with sufficient finely dividedlactose to provide a total amount of 580 to 590 mg to fill a size 0 hardgel capsule.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

1. A method of treating benign prostatic hyperplasia (BPH), comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I)

is W is selected from the group consisting of O, S and NR^(F); wherein R^(F) is selected from the group consisting of hydrogen, hydroxy, C₁₋₄alkyl, C₁₋₄alkoxy, cyano and —SO₂—C₁₋₄alkyl; R^(l) is selected from the group consisting of C₁₋₄alkyl and halogenated C₁₋₄alkyl; R² is selected from the group consisting of hydrogen, C₁₋₄alkyl, halogenated C₁₋₄alkyl, —C(O)O—C₁₋₄ alkyl, —C(O)—C₁₋₄ alkyl and —C(O)-(halogenated C₁₋₄alkyl); a is an integer from 0 to 1; R³ is selected from the group consisting of hydrogen, halogen, C₁₋₄ alkyl, halogenated C₁₋₄alkyl, cyano, nitro, amino, benzyl, —O-phenyl, —C(O)-phenyl, —S(O)₀₋₂—C₁₋₄alkyl, C₁₋₄ alkylamino, di C₁₋₄ alkylamino, —O—C₁₋₄ alkyl, —NR^(A)—C(O)—C₁₋₄ alkyl and —S(O)₀₋₂-phenyl, wherein R^(A) is either hydrogen or C₁₋₄ alkyl; R⁴ is selected from the group consisting of hydrogen, halogen, C₁₋₄ alkyl, halogenated C ₁₋₄ alkyl, cyano, nitro, amino, benzyl, —O-phenyl, —C(O)-phenyl, —S(O)₀₋₂—C₁₋₄alkyl, C₁₋₄ alkylamino, di C₁₋₄ alkylamino, —O—C₁₋₄ alkyl, —NR^(B)—C(O)—C₁₋₄ alkyl and —S(O)₀₋₂-phenyl, wherein R^(B) is either hydrogen or C₁₋₄ alkyl; provided that at least one of R³ or R⁴ is other than hydrogen; R⁶ and R⁷ are each independently selected from the group consisting of hydrogen, halogen, C₁₋₄alkyl, C₂₋₄ alkenyl, C₁₋₄alkoxy, cyano, —C(O)O—C₁₋₄alkyl and —S(O)_(0-2—C) ₁₋₄alkyl;

is selected from the group consisting of

wherein R^(5′) is selected from the group consisting of halogen and C₁₋₄alkyl; and wherein R¹⁰ is selected from hydrogen, C₁₋₄alkyl, benzyl or —C(O)—CF₃; R⁵ is selected from the group consisting of hydrogen, carboxy, alkyl, halogenated C₁₋₄alkyl, hydroxy substituted C₁₋₄alkyl, cycloalkyl, aryl, aralkyl, —C(O)—C₁₋₄alkyl, —C(O) -(halogenated C₁₋₄alkyl), —C(O)O—C₁₋₄alkyl, —C(O)O-aryl, —C₁₋₄alkyl-S(O)₀₋₂—C₁₋₄alkyl, t-butyl-dimethyl-silyl and trimethylsilyl; wherein the aryl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C₁₋₄alkyl, C₁₋₄alkoxy, halogenated C₁₋₄alkyl, cyano, nitro, —NR^(C)—C(O)—C₁₋₄alkyl, NR^(C)—C(O)-(halogenated C₁₋₄alkyl), —C(O)O—C₁₋₄alkyl, trimethyl-silyl and t-butyl-dimethyl-silyloxy; wherein R^(C) and R^(D) are each independently selected from hydrogen or C₁₋₄alkyl; or a pharmaceutically acceptable salt thereof.
 2. The method of claim 1, wherein the compound further comprises W is selected from the group consisting of O, S and NR^(F); wherein R^(F) is selected from the group consisting of hydrogen, hydroxy, C₁₋₄alkyl, C₁₋₂alkoxy, cyano and —SO₂—C₁₋₂alkyl; R^(l) is selected from the group consisting of C₁₋₄alkyl and halogenated C₁₋₂alkyl; R² is selected from the group consisting of hydrogen, C₁₋₄alkyl, halogenated C₁₋₂alkyl and —C(O)-(halogenated C₁₋₂alkyl); a is an integer from 0 to 1; R³ is selected from the group consisting of hydrogen, halogen, halogenated C₁₋₄alkyl and cyano; R⁴ is selected from the group consisting of halogen, cyano, nitro, benzyl, —O -phenyl, —C(O)-phenyl, —S(O)₀₋₂—C₁₋₄alkyl and —S(O)₀₋₂-phenyl; R⁶ and R⁷ are each independently selected from the group consisting of hydrogen, halogen, C₁₋₂alkyl, C₁₋₂alkoxy, cyano, —C(O)O—C ₁₋₂alkyl, —S—C₁₋₄alkyl and —SO₂—C₁₋₄alkyl;

is selected from the group consisting of

wherein R^(5′) is halogen; and wherein R¹⁰ is selected from hydrogen, C₁₋₄alkyl, benzyl or —C(O)—CF₃; R⁵ is selected from the group consisting of hydrogen, carboxy, C₁₋₄alkyl, halogenated C₁₋₄alkyl, —C₁₋₄alkyl-OH, cycloalkyl, aryl, aralkyl, C₁₋₄alkyl-S—C₁₋₄alkyl, —C(O)O—C₁₋₄alkyl, —C(O)-(halogenated C₁₋₄alkyl) and trimethylsilyl; wherein the aryl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from hydroxy, halogen, C ₁₋₄alkyl, —O—C ₁₋₄alkyl, —C(O)O—C ₁₋₄alkyl, —NH—C (O)—C ₁₋₄alkyl, —NH—C(O)-(halogenated C₁₋₄alkyl) or t-butyl-dimethyl-silyloxy; or a pharmaceutically acceptable salt thereof.
 3. The method as in claim 2, wherein W is selected from the group consisting of O, S and NR^(F); wherein R^(F) is selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, methoxy, cyano and —SO₂-methyl; R¹ is selected from the group consisting of methyl, (S)-methyl, (R)-methyl, ethyl, n-propyl and trifluoromethyl; R² is selected from the group consisting of hydrogen, methyl, trifluoroethyl and —C(O)—CF₃; a is an integer from 0 to 1; R³ is selected from the group consisting of hydrogen, chloro, trifluoromethyl and cyano; R⁴ is selected from the group consisting of chloro, bromo, cyano, nitro, benzyl, —O-phenyl, —S-phenyl, —C(O)-phenyl, —SO₂-methyl and —SO₂-phenyl; R⁶ is selected from the group consisting of hydrogen, chloro, iodo, ethyl, methoxy, cyano, —C(O)O-methyl, —S-ethyl, —S-t-butyl and —SO₂-ethyl; R⁷ is selected from the group consisting of hydrogen, chloro and ethyl;

is selected from the group consisting of

wherein R^(5′) is chloro; and wherein R¹⁰ is selected from hydrogen, methyl, ethyl, benzyl or —C(O)—CF₃; R⁵ is selected from the group consisting of hydrogen, carboxy, methyl, ethyl, n-propyl, isopropyl, isobutyl, t-butyl, trifluoromethyl, 2,2,2-trifluoro-ethyl, 1,1,2,2,2-pentafluoro-ethyl, hydroxy-methyl-, 2-hydroxy-phenyl, 4-fluorophenyl, 3,4-difluorophenyl, 2,3,4,5,6-pentafluorophenyl, 4-ethylphenyl, 4-methoxy-phenyl, 2-hydroxy-3-fluoro-phenyl, 2-fluoro-3-hydroxy-phenyl, 3-methyl-4-fluoro-phenyl, cyclopentyl, cyclohexyl, 4-methoxy-carbonyl-phenyl, 3-methyl-carbonyl-amino-phenyl, 4-methyl-carbonyl-amino-phenyl, 4-(trifluoromethyl-carbonyl-amino)-phenyl, 2-(t-butyl-dimethyl-silyloxy)-3-fluoro-phenyl, t-butyl-dimethyl-silyloxy-phenyl, 4-methyl-carbonyl-amino-benzyl, 4-methyl-carbonyl-amino-phenyl, 2-furyl, 2-thienyl, 3-pyridyl, 2-tetrahydrofuryl, methyl-thio-ethyl-, ethyl-thio-ehyl-, ethoxy-carbonyl-, t-butoxy-carbonyl-, trifluoromethyl-carbonyl- and trimethylsilyl; or a pharmaceutically acceptable salt thereof.
 4. The method as in claim 2, wherein W is selected from the group consisting of O, S and NR^(F); wherein R^(F) is selected from the group consisting of hydrogen, hydroxy, cyano, C₁₋₄alkyl, C₁₋₂alkoxy and —SO₂—C₁₋₂alkyl; R^(l) is selected from the group consisting of C₁₋₄alkyl and halogenated C₁₋₄alkyl; R² is selected from the group consisting of hydrogen, C₁₋₄alkyl, halogenated C₁₋₂alkyl and —C(O)-(halogenated C₁₋₂alkyl); a is an integer from 0 to 1; R³ is selected from the group consisting of hydrogen, halogen, halogenated C₁₋₄alkyl and cyano; R⁴ is selected from the group consisting of halogen, cyano, nitro, benzyl, —O -phenyl, —C(O)-phenyl, —S(O)₀₋₂—C₁₋₄alkyl and —S(O)₀₋₂-phenyl; R⁶ and R⁷ are each independently selected from the group consisting of hydrogen, halogen, C₁₋₂alkyl, C₁₋₂alkoxy, cyano, —C(O)O—C₁₋₂alkyl, —S—C₁₋₄alkyl and —SO₂—C₁₋₄alkyl;

is selected from the group consisting of

wherein R^(5′) is halogen; and wherein R¹⁰ is selected from the group consisting of hydrogen, C₁₋₄alkyl, benzyl and —C(O)—CF₃; R⁵ is selected from the group consisting of hydrogen, carboxy, C₁₋₄alkyl, halogenated C₁₋₄alkyl, —C₁₋₄alkyl-OH, cycloalkyl, aryl, aralkyl, —C₁₋₄alkyl-S—C₁₋₄alkyl, —C(O)O—C₁₋₄alkyl, —C(O)-(halogenated C₁₋₄alkyl) and trimethylsilyl; wherein the aryl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from hydroxy, halogen, C₁₋₄alkyl, —O—C₁₋₄alkyl, —C(O)O—C₁₋₄alkyl, —NH—C(O)—C ₁₋₄alkyl, —NH-C(O)-(halogenated C₁₋₄alkyl) or t-butyl-dimethyl-silyloxy; or a pharmaceutically acceptable salt thereof.
 5. The method as in claim 4, wherein W is selected from the group consisting of O, S and NR^(F); wherein R^(F) is selected from the group consisting of hydrogen, methyl, ethyl, methoxy, cyano and —SO₂-methyl; R^(l) is selected from the group consisting of methyl, (S)-methyl, (R)-methyl, ethyl, n-propyl and trifluoromethyl; R² is selected from the group consisting of hydrogen, methyl, trifluoromethyl and —C(O)—CF₃; a is an integer from 0 to 1; R³ is selected from the group consisting of hydrogen, chloro, trifluoromethyl and cyano; R⁴ is selected from the group consisting of chloro, bromo, cyano, nitro, benzyl, —O-phenyl, —S-phenyl, —C(O)-phenyl, —SO₂-methyl and —SO₂-phenyl; R⁶ is selected from the group consisting of hydrogen, chloro, iodo, ethyl, methoxy, cyano, —C(O)O-methyl, —S-ethyl, —S-t-butyl and —SO₂-ethyl; R⁷ is selected from the group consisting of hydrogen. chloro and ethyl:

is selected from the group consisting of

wherein R^(5′) is chloro; and wherein R¹⁰ is selected from hydrogen, methyl, ethyl, benzyl or —C(O)—CF₃; R⁵ is selected from the group consisting of hydrogen, carboxy, methyl, ethyl, n-propyl, isopropyl, isobutyl, t-butyl, trifluoromethyl, 2,2,2-trifluoro-ethyl, 1,1,2,2,2-pentafluoro-ethyl, hydroxy-methyl-, 2-hydroxy-phenyl, 4-fluorophenyl, 3,4-difluorophenyl, 2,3,4,5,6-pentafluorophenyl, 4-ethylphenyl, 4-methoxy-phenyl, 2-hydroxy-3-fluoro-phenyl, 2-fluoro-3-hydroxy-phenyl, 3-methyl-4-fluoro-phenyl, cyclopentyl, cyclohexyl, 4-methoxy-carbonyl-phenyl, 3-methyl-carbonyl-amino-phenyl, 4-methyl-carbonyl-amino-phenyl, 4-(trifluoromethyl-carbonyl-amino)-phenyl, 2-(t-butyl-dimethyl-silyloxy)-3-fluoro-phenyl, t-butyl-dimethyl-silyloxy-phenyl, 4-methyl-carbonyl-amino-benzyl, 4-methyl-carbonyl-amino-phenyl, 2-furyl, 2-thienyl, 3-pyridyl, 2-tetrahydrofuryl, methyl-thio-ethyl-, ethyl-thio-ehyl-, ethoxy-carbonyl-, t-butoxy-carbonyl-, trifluoromethyl-carbonyl- and trimethylsilyl; or a pharmaceutically acceptable salt thereof.
 6. The method as in claim 3, wherein W is selected from the group consisting of O, NH, N(OH), N(ethyl) and N(methoxy); R^(l) is selected from the group consisting of methyl, (R)-methyl, (S)-methyl, ethyl and trifluoromethyl; R² is selected from the group consisting of hydrogen and methyl; a is an integer from 0 to 1; R³ is selected from the group consisting of hydrogen and trifluoromethyl; R⁴ is selected from the group consisting of bromo, cyano, nitro and —SO₂-phenyl; R⁶ is selected from the group consisting of hydrogen, iodo, chloro and —S-ethyl; R⁷ is selected from the group consisting of hydrogen and ethyl;

is selected from the group consisting of

wherein R^(5′) is chloro; and wherein R¹⁰ is selected from the group consisting of hydrogen, methyl and ethyl; R⁵ is selected from the group consisting of methyl, trifluoromethyl, 1,1,2,2,2-pentafluoro-ethyl, —C(O)O-ethyl, 4-methyl-carbonyl-amino-phenyl, 4-trifluoromethyl-carbonyl-amino-phenyl and 4-methyl-carbonyl-amino-benzyl; or a pharmaceutically acceptable salt thereof.
 7. The method as in claim 3, wherein W is selected from the group consisting of O and N(ethyl); R^(l) is methyl; R² is selected from the group consisting of hydrogen and methyl; a is an integer from 0 to 1; R³ is trifluoromethyl; R⁴ is selected from the group consisting of chloro, cyano and nitro; R⁶ is selected from the group consisting of hydrogen, chloro, ethyl and —SO₂-ethyl; R⁷ is selected from the group consisting of hydrogen, chloro and ethyl;

wherein R¹⁰ is selected from the group consisting of hydrogen and ethyl; R⁵ is selected from the group consisting of hydrogen, n-propyl, isopropyl, trifluoromethyl, 4-fluorophenyl, 3,4-difluorophenyl, 2,3,4,5,6-entafluorophenyl, 4-methoxyphenyl, 4-ethylphenyl, cyclohexyl, 2-furyl and 2-thienyl; or a pharmaceutically acceptable salt thereof.
 8. The method as in claim 3, wherein the compound is selected from the group consisting of 3-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide; 3-Ethyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid 4-cyano-3-trifluoromethyl-phenyl)-amide; 5-(4-Acetylamino-phenyl)-3-methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide; 5-(4-Acetylamino-phenyl)-3-methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-nitro-3-trifluoromethyl-phenyl)-amide; 3-Methyl-5[4-(2,2,2-trifluoro-acetylamino)-phenyl]-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-nitro-3-trifluoromethyl-phenyl)-amide; and pharmaceutically acceptable salts thereof.
 9. The method of claim 8, wherein the compound is selected from the group consisting of (R)-3-Methyl-5-trifluoromethy1-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide; (S)-3-Methyl-5-trifluoromethy1-3 ,4-dihydro -2H-pyrazole-3- carboxylic acid (4-cyano -3-trifluoromethyl -pheny1)- amide; and pharmaceutically acceptable salts thereof.
 10. A method of claim 1 comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising a pharmaceutically acceptable carrier and a compound of Formula (I). 